Process for neuroprotective therapy for glaucoma

ABSTRACT

Providing neuroprotective therapy for glaucoma includes generating a micropulsed laser light beam having parameters and characteristics, including pulse length, power, and duty cycle, selected to create a therapeutic effect with no visible laser lesions or tissue damage to the retina. The laser light beam is applied to retinal and/or foveal tissue of an eye having glaucoma or a risk of glaucoma to create a therapeutic effect to the retinal and/or foveal tissue exposed to the laser light beam without destroying or permanently damaging the retinal and/or foveal tissue and improve function or condition of an optic nerve and/or retinal ganglion cells of the eye.

RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 15/232,320,filed Aug. 9, 2016 which is a continuation-in-part of U.S. applicationSer. No. 15/148,842, filed May 6, 2016 which is a continuation-in-partof U.S. application Ser. No. 14/921,890, filed Oct. 23, 2015 (now U.S.Pat. No. 9,381,116), which is a continuation-in-part of U.S. applicationSer. No. 14/607,959, filed Jan. 28, 2015 (now U.S. Pat. No. 9,168,174),which is a continuation-in-part of U.S. application Ser. No. 13/798,523,filed Mar. 13, 2013, (now U.S. Pat. No. 10,219,947) which is acontinuation-in-part of U.S. application Ser. No. 13/481,124, filed May25, 2012 (now U.S. Pat. No. 9,381,115); and is also acontinuation-in-part of U.S. application Ser. No. 15/188,608, filed Jun.21, 2016, which is a continuation of U.S. application Ser. No.13/481,124, filed May 25, 2012 (now U.S. Pat. No. 9,381,115); and is acontinuation-in-part of U.S. application Ser. No. 13/798,523, filed Mar.13, 2013, (now U.S. Pat. No. 10,219,947) which is a continuation-in-partof U.S. application Ser. No. 13/481,124, filed May 25, 2012 (now U.S.Pat. No. 9,381,115).

BACKGROUND OF THE INVENTION

The present invention generally relates to therapies for glaucoma. Moreparticularly, the present invention is directed to a system and processfor providing harmless, subthreshold phototherapy or photostimulation ofthe retina that improves function or condition of an optic nerve of theeye and provides neuroprotective therapy for glaucoma.

Complications of diabetic retinopathy remain a leading cause of visionloss in people under sixty years of age. Diabetic macular edema is themost common cause of legal blindness in this patient group. Diabetesmellitus, the cause of diabetic retinopathy, and thus diabetic macularedema, is increasing in incidence and prevalence worldwide, becomingepidemic not only in the developed world, but in the developing world aswell. Diabetic retinopathy may begin to appear in persons with Type I(insulin-dependent) diabetes within three to five years of diseaseonset. The prevalence of diabetic retinopathy increases with duration ofdisease. By ten years, 14%-25% of patients will have diabetic macularedema. By twenty years, nearly 100% will have some degree of diabeticretinopathy. Untreated, patients with clinically significant diabeticmacular edema have a 32% three-year risk of potentially disablingmoderate visual loss.

Until the advent of thermal retinal photocoagulation, there wasgenerally no effective treatment for diabetic retinopathy. Usingphotocoagulation to produce photothermal retinal burns as a therapeuticmaneuver was prompted by the observation that the complications ofdiabetic retinopathy were often less severe in eyes with preexistingretinal scarring from other causes. The Early Treatment of DiabeticRetinopathy Study demonstrated the efficacy of argon laser macularphotocoagulation in the treatment of diabetic macular edema.Full-thickness retinal laser burns in the areas of retinal pathologywere created, visible at the time of treatment as white or gray retinallesions (“suprathreshold” retinal photocoagulation). With time, theselesions developed into focal areas of chorioretinal scarring andprogressive atrophy.

With visible endpoint photocoagulation, laser light absorption heatspigmented tissues at the laser site. Heat conduction spreads thistemperature increase from the retinal pigment epithelium and choroid tooverlying non-pigmented and adjacent unexposed tissues. Laser lesionsbecome visible immediately when damaged neural retina overlying thelaser sight loses its transparency and scatters white ophthalmoscopiclight back towards the observer.

There are different exposure thresholds for retinal lesions that arehaemorrhagic, ophthalmoscopically apparent, or angiographicallydemonstrable. A “threshold” lesion is one that is barely visibleophthalmoscopically at treatment time, a “subthreshold” lesion is onethat is not visible at treatment time, and “suprathreshold” lasertherapy is retinal photocoagulation performed to a readily visibleendpoint. Traditional retinal photocoagulation treatment requires avisible endpoint either to produce a “threshold” lesion or a“suprathreshold” lesion so as to be readily visible and tracked. Infact, it has been believed that actual tissue damage and scarring arenecessary in order to create the benefits of the procedure. The gray towhite retinal burns testify to the thermal retinal destruction inherentin conventional threshold and suprathreshold photocoagulation.Photocoagulation has been found to be an effective means of producingretinal scars, and has become the technical standard for macularphotocoagulation for diabetic macular edema for nearly 50 years.

With reference now to FIG. 1, a diagrammatic view of an eye, generallyreferred to by the reference number 10, is shown. When usingphototherapy, the laser light is passed through the patient's cornea 12,pupil 14, and lens 16 and directed onto the retina 18. The retina 18 isa thin tissue layer which captures light and transforms it into theelectrical signals for the brain. It has many blood vessels, such asthose referred to by reference number 20, to nourish it. Various retinaldiseases and disorders, and particularly vascular retinal diseases suchas diabetic retinopathy, are treated using conventional thermal retinalphotocoagulation, as discussed above. The fovea/macula region, referredto by the reference number 22 in FIG. 1, is a portion of the eye usedfor color vision and fine detail vision. The fovea is at the center ofthe macula, where the concentration of the cells needed for centralvision is the highest. Although it is this area where diseases such asage-related macular degeneration are so damaging, this is the area whereconventional photocoagulation phototherapy cannot be used as damagingthe cells in the foveal area can significantly damage the patient'svision. Thus, with current convention photocoagulation therapies, thefoveal region is avoided.

That iatrogenic retinal damage is necessary for effective lasertreatment of retinal vascular disease has been universally accepted foralmost five decades, and remains the prevailing notion. Althoughproviding a clear advantage compared to no treatment, current retinalphotocoagulation treatments, which produce visible gray to white retinalburns and scarring, have disadvantages and drawbacks. Conventionalphotocoagulation is often painful. Local anesthesia, with its ownattendant risks, may be required. Alternatively, treatment may bedivided into stages over an extended period of time to minimizetreatment pain and post-operative inflammation. Transient reduction invisual acuity is common following conventional photocoagulation.

In fact, thermal tissue damage may be the sole source of the manypotential complications of conventional photocoagulation which may leadto immediate and late visual loss. Such complications includeinadvertent foveal burns, pre- and sub-retinal fibrosis, choroidalneovascularization, and progressive expansion of laser scars.Inflammation resulting from the tissue destruction may cause orexacerbate macular edema, induced precipitous contraction offibrovascular proliferation with retinal detachment and vitreoushemorrhage, and cause uveitis, serous choroidal detachment, angleclosure or hypotony. Some of these complications are rare, while others,including treatment pain, progressive scar expansion, visual field loss,transient visual loss and decreased night vision are so common as to beaccepted as inevitable side-effects of conventional laser retinalphotocoagulation. In fact, due to the retinal damage inherent inconventional photocoagulation treatment, it has been limited in densityand in proximity to the fovea, where the most visually disablingdiabetic macular edema occurs.

Notwithstanding the risks and drawbacks, retinal photocoagulationtreatment, typically using a visible laser light, is the currentstandard of care for proliferative diabetic retinopathy, as well asother retinopathy and retinal diseases, including diabetic macular edemaand retinal venous occlusive diseases which also respond well to retinalphotocoagulation treatment. In fact, retinal photocoagulation is thecurrent standard of care for many retinal diseases, including diabeticretinopathy.

Another problem is that the treatment requires the application of alarge number of laser doses to the retina, which can be tedious andtime-consuming. Typically, such treatments call for the application ofeach dose in the form of a laser beam spot applied to the target tissuefor a predetermined amount of time, from a few hundred milliseconds toseveral seconds. Typically, the laser spots range from 50-500 microns indiameter. Their laser wavelength may be green, yellow, red or eveninfrared. It is not uncommon for hundreds or even in excess of onethousand laser spots to be necessary in order to fully treat the retina.The physician is responsible for insuring that each laser beam spot isproperly positioned away from sensitive areas of the eye, such as thefovea, that could result in permanent damage. Laying down a uniformpattern is difficult and the pattern is typically more random thangeometric in distribution. Point-by-point treatment of a large number oflocations tends to be a lengthy procedure, which frequently results inphysician fatigue and patient discomfort.

U.S. Pat. No. 6,066,128, to Bahmanyar describes a method of multi-spotlaser application, in the form of retinal-destructive laserphotocoagulation, achieved by means of distribution of laser irradiationthrough an array of multiple separate fiber optic channels and microlenses. While overcoming the disadvantages of a point-by-point laserspot procedure, this method also has drawbacks. A limitation of theBahmanyar method is differential degradation or breakage of the fiberoptics or losses due to splitting the laser source into multiple fibers,which can lead to uneven, inefficient and/or suboptimal energyapplication. Another limitation is the constraint on the size anddensity of the individual laser spots inherent in the use of an opticalsystem of light transmission fibers in micro lens systems. Themechanical constraint of dealing with fiber bundles can also lead tolimitations and difficulties focusing and aiming the multi-spot array.

U.S. Patent Publication 2010/0152716 A1 to Previn describes a differentsystem to apply destructive laser irradiation to the retina using alarge retinal laser spot with a speckle pattern, oscillated at a highfrequency to homogenize the laser irradiance throughout the spot.However, a problem with this method is the uneven heat buildup, withhigher tissue temperatures likely to occur toward the center of thelarge spot. This is aggravated by uneven heat dissipation by the ocularcirculation resulting in more efficient cooling towards the margins ofthe large spot compared to the center. That is, the speckle patternbeing oscillated at a high frequency can cause the laser spots to beoverlapping or so close to one another that heat builds up andundesirable tissue damage occurs. Previn's speckle technique achievesaveraging of point laser exposure within the larger exposure via therandom fluctuations of the speckle pattern. However, such averagingresults from some point exposures being more intense than others,whereas some areas within the exposure area may end with insufficientlaser exposure, whereas other areas will receive excessive laserexposure. In fact, Previn specifically notes the risk of excessiveexposure or exposure of sensitive areas, such as the fovea, which shouldbe avoided with this system. Although these excessively exposed spotsmay result in retinal damage, Previn's invention is explicitly intendedto apply damaging retinal photocoagulation to the retina, other than thesensitive area such as the fovea.

All conventional retinal photocoagulation treatments, including thosedescribed by Previn and Bahmanyar, create visible endpoint laserphotocoagulation in the form of gray to white retinal burns and lesions,as discussed above.

Recently, the inventor has discovered that subthreshold photocoagulationin which no visible tissue damage or laser lesions were detectable byany known means including ophthalmoscopy; infrared, color, red-free orautofluorescence fundus photography in standard or retro-mode;intravenous fundus fluorescein or indocyanine green angiographically, orSpectral-domain optical coherence tomography at the time of treatment orany time thereafter has produced similar beneficial results andtreatment without many of the drawbacks and complications resulting fromconventional visible threshold and suprathreshold photocoagulationtreatments. It has been determined that with the proper operatingparameters, subthreshold photocoagulation treatment can be, and mayideally be, applied to the entire retina, including sensitive areas suchas the fovea, without visible tissue damage or the resulting drawbacksor complications of conventional visible retinal photocoagulationtreatments. In fact, the inventor has found that the treatment is notonly harmless, it uniquely improves function of the retina and fovea ina wide variety of retinopathies immediately and is thus restorative tothe retina. Moreover, by desiring to treat the entire retina, orconfluently treat portions of the retina, laborious and time-consumingpoint-by-point laser spot therapy can be avoided. In addition, theinefficiencies and inaccuracies inherent to invisible endpoint lasertreatment resulting in suboptimal tissue target coverage can also beavoided.

Glaucoma is a group of eye diseases which result in damage to the opticnerve and vision loss. The most common type is open-angle glaucoma,which develops slowly over time and there is no pain. Side vision maybegin to decrease followed by central vision, resulting in blindness ifnot treated. If treated early, however, it is possible to slow or stopthe progression of the disease. The underlying cause of open-angleglaucoma remains unclear, however, the major risk factor for mostglaucoma and the focus of treatment is increased intraocular pressure(IOP). The goal of these treatments is to decrease eye pressure.

While elevated 10P has been historically implicated in the developmentof open-angle glaucoma (OAG), nearly half of all patients present with,or progress, despite 10P in the normal range. Furthermore, despitelowering 10P, glaucomatous optic nerve damage and vision loss may stillprogress. Many patients present with glaucomatous optic nerve cuppingand vision loss despite normal or even low normal 10P. Theseobservations have led to theories suggesting OAG may, in part, representa primary optic neuropathy or perhaps an ocular manifestation ofotherwise unrecognized central nervous system, or other, disease. Theseconcerns, and the recognition that IOP lowering alone may not besufficient to prevent visual loss, have led to increased interest inmeasures, termed “neuroprotection”, to improve the function and healthof the optic nerve, to make it less vulnerable to progressive atrophy.By improving optic nerve function, it is hoped that progressivedegeneration may be slowed or stopped as a compliment to 10P reduction,reducing the risk of visual loss. While a number of therapies holdneuroprotective promise, none has thus far demonstrated clear clinicalbenefits beyond IOP reduction.

Accordingly, there is a continuing need for a system and method forproviding a therapy which provides neuroprotection to the optic nerve soas to improve the optic nerve function or condition. There is also acontinuing need for such a method and system which can be administeredto the retina which does not create detectable retinal burns or lesionsand thus does not permanently damage or destroy the retinal tissue,while improving the function and health of the retinal ganglion cellsand/or the optic nerve. Such a system and method should be able to beapplied to the entire retina, including sensitive areas such as thefovea, without visible tissue damage or the resulting drawbacks orcomplications of conventional visible retinal photocoagulationtreatments. There is an addition need for such a system and method fortreating the entire retina, or at least portion of the retina, in a lesslaborious and time-consuming manner. The present invention fulfillsthese needs and provides other related advantages.

SUMMARY OF THE INVENTION

The present invention resides in a process and system for treatingretinal diseases and disorders and providing neuroprotective treatmentin glaucoma by means of harmless, restorative subthresholdphotocoagulation phototherapy. A laser light beam having predeterminedoperating parameters and characteristics is applied to the retinaland/or foveal tissue of an eye having glaucoma or a risk of glaucoma tocreate a therapeutic effect to the retinal and/or foveal tissue exposedto the laser light beam without destroying or permanently damaging theretinal and/or foveal tissue, while improving the function or conditionof an optic nerve or retinal ganglion cells of the eye.

In accordance with the present invention, a system for providingglaucoma neuroprotective treatment comprises a laser console generatinga micropulsed laser light beam. The laser light beam is passed throughan optical lens or mask to optically shape the laser light beam. Acoaxial wide-field non-contact digital optical viewing camera projectsthe laser light beam to an area of a desired site of a retina and/orfovea of an eye for performing retinal phototherapy or photostimulation.An optical scanning mechanism controllably directs the light beam ontothe retina and/or fovea to provide a therapeutic effect to the retinaland/or foveal tissue and improve optical nerve or retinal ganglion cellfunction or condition.

The laser light beam has characteristics of providing a therapeuticeffect to retinal and/or foveal tissue without destroying or permanentlydamaging the retinal or foveal tissue. The laser light beam typicallyhas a wavelength greater than 532 nm. The laser light radiant beam mayhave an infrared wavelength such as between 750 nm-1300 nm, andpreferably approximately 810 nm. The laser has a duty cycle of less than10%, and preferably a duty cycle of 5% or less. The exposure envelope ofthe laser is generally 500 milliseconds or less, and the micropulsefrequency is preferably 500 Hz. The light beam may have an intensitybetween 100-590 watts per square centimeter, and preferablyapproximately 350 watts per square centimeter. The laser console maygenerate a plurality of micropulsed light beams, at least a plurality ofthe light beams having different wavelengths.

The optical lens or mask may optically shape the light beam from thelaser console into a geometric object or pattern. This may be done bydiffractive optics to simultaneously generate a plurality of therapeuticbeams or spots from the laser light beam, wherein the plurality of spotsare projected from the coaxial wide-field non-contact digital opticalviewing camera to at least a portion of the desired treatment area ofthe retina and/or fovea.

The laser light beam is controllably moved, such as using an opticalscanning mechanism, to achieve complete coverage of the desired site forperforming retinal phototherapy or photostimulation. The opticalscanning mechanism may controllably move the light beam untilsubstantially all of the retina and fovea have been exposed to the lightbeam. The laser light beam may be selectively applied to disease markerson the desired site for performing retinal phototherapy orphotostimulation. The laser light beam may be projected to at least aportion of the center of the desired site for performing retinalphototherapy or photostimulation. A fundus image of the desired site forperforming retinal phototherapy or photostimulation may be displayedparallel to or super imposed over a result image from a retinaldiagnostic modality.

The laser light beam or geometric object or pattern is controllablymoved by the optical scanning mechanism to different treatment areasbetween micropulses of the laser light beam. The laser light beam iscontrollably returned to the previously treated or exposed area withinless than a second from the previous application of the laser light tothe area. More typically, the laser light beam is returned to thepreviously treated or exposed area within one millisecond to threemilliseconds.

In accordance with the present invention, a process for performingretinal phototherapy or photostimulation comprises the step ofgenerating a laser light beam that creates a therapeutic effect toretinal and/or foveal tissue exposed to the laser light withoutdestroying or permanently damaging the retinal or foveal tissue.Parameters of the generated laser light beam, including the pulselength, power, and duty cycle are selected to create a therapeuticeffect with no visible laser lesions or tissue damage detectedophthalmoscopically or angiographically or to any currently known meansafter treatment. The laser light beam has a wavelength greater than 532nm and a duty cycle of less than 10%. The laser light beam may have awavelength of between 750 nm and 1300 nm. The laser light beam may havea duty cycle of approximately 5% or less. The laser light beam may havean intensity of 100-590 watts per square centimeter, and a pulse lengthof 500 milliseconds or less.

The laser light beam is applied to the retinal and/or foveal tissue ofan eye having glaucoma or risk of glaucoma to create a therapeuticeffect to the retinal and/or foveal tissue exposed to the laser lightbeam without destroying or permanently damaging the retinal and/orfoveal tissue and improve function or condition of an optic nerve orretinal ganglion cells of the eye. The laser light beam may be appliedto both retinal and foveal tissue of the eye, and the entire retina,including the fovea, may be treated without damaging retinal or fovealtissue while still providing the benefits of the present invention.

A plurality of laser light beams from a plurality of micropulsed lasershaving different wavelengths may be applied onto the retinal and/orfoveal tissue of the eye.

A plurality of spaced apart treatment laser spots may be formed andsimultaneously applied to the retinal and/or foveal tissue of the eye. Aplurality of laser light spots may be controllably moved to treatadjacent retinal tissue. A single micropulse of laser light is less thana millisecond in duration, and may be between 50 microseconds to 100microseconds in duration.

In accordance with the present invention, after a predetermined intervalof time, within a single treatment session, the laser light spots arereapplied to a first treatment area of the retina and/or fovea. Duringthe interval of time between the laser light applications to the firsttreatment area, the laser light is applied to at least one other area ofthe retina and/or fovea to be treated that is spaced apart from thefirst treatment area. The adjacent areas are separated by at least apredetermined minimum distance to avoid thermal tissue damage. Theinterval of time between laser light applications to a treatment area isless than one second, and more typically between one and threemilliseconds. The laser light spots are repeatedly applied to each ofthe areas to be treated until a predetermined number of laser lightapplications to each area to be treated has been achieved. Thepredetermined number of laser light applications to each treatment areamay be between 50 to 200, and more typically 75 to 150. Typically, thelaser light is reapplied to previously treated areas in sequence.

Other features and advantages of the present invention will becomeapparent from the following more detailed description, taken inconjunction with the accompanying drawings, which illustrate, by way ofexample, the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate the invention. In such drawings:

FIG. 1 is a cross-sectional diagrammatic view of a human eye;

FIGS. 2A-2D are graphic representations of the effective surface area ofvarious modes of retinal laser treatment in accordance with the priorart;

FIGS. 3A and 3B are graphic representations of effective surface areasof retinal laser treatment, in accordance with the present invention;

FIG. 4 is an illustration of a cross-sectional view of a diseased humanretina before treatment with the present invention;

FIG. 5 is a cross-sectional view similar to FIG. 10, illustrating theportion of the retina after treatment using the present invention;

FIG. 6 is a diagrammatic view illustrating a system used for treating aretinal disease or disorder in accordance with the present invention;

FIG. 7 is a diagrammatic view of an exemplary optical lens or mask usedto generate a geometric pattern, in accordance with the presentinvention;

FIG. 8 is a diagrammatic view illustrating an alternate embodiment of asystem used for treating a retinal disease or disorder in accordancewith the present invention;

FIG. 9 is a diagrammatic view illustrating yet another alternateembodiment of a system used for treating a retinal disease or disorderin accordance with the present invention;

FIG. 10 is a top plan view of an optical scanning mechanism, used inaccordance with the present invention;

FIG. 11 is a partially exploded view of the optical scanning mechanismof FIG. 10, illustrating the various component parts thereof;

FIG. 12 illustrates controlled offset of exposure of an exemplarygeometric pattern grid of laser spots to treat the retina;

FIG. 13 is a diagrammatic view illustrating the units of a geometricobject in the form of a line controllably scanned to treat an area ofthe retina;

FIG. 14 is a diagrammatic view similar to FIG. 13, but illustrating thegeometric line or bar rotated to treat an area of the retina;

FIGS. 15A-15D are diagrammatic views illustrating the application oflaser light to different treatment areas during a predetermined intervalof time, within a single treatment session, and reapplying the laserlight to previously treated areas, in accordance with the presentinvention.

FIGS. 16-18 are graphs depicting the relationship of treatment power andtime in accordance with embodiments of the present invention;

FIG. 19 is a front view of a camera including an iris aperture of thepresent invention;

FIG. 20 is a front view of a camera including an LCD aperture of thepresent invention;

FIGS. 21 and 22 are graphs depicting the visual evoked potential (VEP)amplitude before and after treatment of the present invention foropen-angle glaucoma;

FIGS. 23 and 24 are pattern electroretinography (PERG) amplitudes beforeand after treatment of the present invention for open-angle glaucoma;and

FIGS. 25 and 26 are graphs depicting Omnifield resolution perimetryvisual areas before and after treatment of the present invention foropen-angle glaucoma.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to a system and process for treatingglaucoma. More particularly, the present invention relates to a systemand process for providing neuroprotective therapy for glaucoma by meansof predetermined parameters producing harmless, yet therapeutic, truesubthreshold photocoagulation.

The inventors' finding that retinal laser treatment that does not causeany laser-induced retinal damage, but can be at least as effective asconventional retinal photocoagulation is contrary to conventionalthinking and practice. Conventional thinking assumes that the physicianmust intentionally create retinal damage as a prerequisite totherapeutically effective treatment.

With reference to FIG. 2, FIGS. 2A-2D are graphic representations of theeffective surface area of various modes of retinal laser treatment forretinal vascular disease. The gray background represents the retina 18which is unaffected by the laser treatment. The black areas 24 are areasof the retina which are destroyed by conventional laser techniques. Thelighter gray or white areas 26 represent the areas of the retinasecondarily affected by the laser, but not destroyed.

FIG. 2A illustrates the therapeutic effect of conventional argon laserretinal photocoagulation. The therapeutic effects attributed tolaser-induced thermal retinal destruction include reduced metabolicdemand, debulking of diseased retina, increased intraocular oxygentension and ultra production of vasoactive cytokines, including vascularendothelial growth factor (VEGF).

With reference to FIG. 2B, increasing the burn intensity of thetraditional laser burn is shown. It will be seen that the burned anddamaged tissue area 24 is larger, which has resulted in a larger “haloeffect” of heated, but undamaged, surrounding tissue 26. Laboratorystudies have shown that increased burn intensity is associated with anenhanced therapeutic effect, but hampered by increased loss offunctional retina and inflammation. However, with reference to FIG. 2C,when the intensity of the conventional argon laser photocoagulation isreduced, the area of the retina 26 affected by the laser but notdestroyed is also reduced, which may explain the inferior clinicalresults from lower-intensity/lower-density or “mild” argon laser gridphotocoagulation compared to higher-intensity/higher-density treatment,as illustrated in FIG. 2B.

With reference to FIG. 2D, it has been found that low-fluencephotocoagulation with short-pulse continuous wave laserphotocoagulation, also known as selective retinal therapy, producesminimal optical and lateral spread of laser photothermal tissue effects,to the extent that the area of the retina affected by the laser but notdestroyed is minimal to nonexistent. Thus, despite damage or completeablation of the directly treated retina 18, the rim of thetherapeutically affected and surviving tissue is scant or absent. Thisexplains the recent reports finding superiority of conventional argonlaser photocoagulation over PASCAL for diabetic retinopathy.

However, the inventor has shown that such thermal retinal damage isunnecessary and questioned whether it accounts for the benefits of theconventional laser treatments. Instead, the inventor has surmised thatthe therapeutic alterations in the retinal pigment epithelium (RPE)cytokine production elicited by conventional photocoagulation comes fromcells at the margins of traditional laser burns, affected but not killedby the laser exposure, referred to by the reference number 26 in FIG. 2.

FIG. 3A represents the use of a low-intensity and low-density laser,such as a micropulsed diode laser in accordance with the invention,sometimes referred to herein as subthreshold diode micropulse lasertreatment (SDM). This creates “true” subthreshold or invisible retinalphotocoagulation, shown graphically for exemplary purposes by thereference number 28, without any visible burn areas 32. All areas of theretinal pigment epithelium 18 exposed to the laser irradiation arepreserved, and available to contribute therapeutically.

The subthreshold retinal photocoagulation, sometimes referred to as“true subthreshold”, of the invention is defined as retinal laserapplications biomicroscopically invisible at the time of treatment.Unfortunately, the term “subthreshold” has often been used in the art todescribe several different clinical scenarios reflecting widely varyingdegrees of laser-induced thermal retinal damage. The use of the term“subthreshold” falls into three categories reflecting common usage andthe historical and morphological evolution of reduced-intensityphotocoagulation for retinal vascular disease toward truly invisiblephototherapy or true subthreshold photocoagulation which the inventionembodies.

“Classical subthreshold” for photocoagulation describes the earlyattempts at laser intensity reduction using conventional continuousargon, krypton, and diode lasers. Although the retinal burns werenotably less obvious than the conventional “threshold” (photocoagulationconfined to the outer retina and thus less visible at time of treatment)or even milder “suprathreshold” (full-thickness retinal photocoagulationgenerally easily visible at the time of treatment), the lesions of“classical” subthreshold photocoagulation were uniformly visible bothclinically and by fundus fluorescein angiography (FFA) at the time oftreatment and thereafter.

“Clinical subthreshold” photocoagulation describes the next epiphany ofevolution of laser-induced retinal damage reduction, describing alower-intensity but persistently damaging retinal photocoagulation usingeither a micropulsed laser or short-pulsed continuous wave laser thatbetter confine the damage to the outer retina and retinal pigmentationepithelium. In “clinical” subthreshold photocoagulation, the laserlesions may in fact be ophthalmoscopically invisible at the time oftreatment, however, as laser-induced retinal damage remains the intendedpoint of treatment, laser lesions are produced which generally becomeincreasingly clinically visible with time, and many, if not all, laserlesions can be seen by FFA, fundus autofluorescence photography (FAF),and/or spectral-domain (SD) optical coherence tomography (OCT) at thetime of treatment and thereafter.

“True” subthreshold photocoagulation, as a result of the presentinvention, is invisible and includes laser treatment non-discernible byany other known means such as FFA, FAF, or even SD-OCT. “Truesubthreshold” photocoagulation is therefore defined as a laser treatmentwhich produces absolutely no retinal damage detectable by any means atthe time of treatment or any time thereafter by known means ofdetection. As such, with the absence of lesions and other tissue damageand destruction, FIGS. 3A and 3B diagrammatically represent the resultof “true”, invisible subthreshold photocoagulation.

Various parameters have been determined to achieve “true” subthresholdor “low-intensity” effective photocoagulation. These include providingsufficient power to produce effective treatment retinal laser exposure,but not too high to create tissue damage or destruction. Truesubthreshold laser applications can be applied singly or to create ageometric object or pattern of any size and configuration to minimizeheat accumulation, but assure uniform heat distribution as well asmaximizing heat dissipation such as by using a low duty cycle. Theinventor has discovered how to achieve therapeutically effective andharmless true subthreshold retinal laser treatment. The inventor hasalso discovered that placement of true subthreshold laser applicationsconfluently and contiguously to the retinal surface improves andmaximizes the therapeutic benefits of treatment without harm or retinaldamage.

The American Standards Institute (ANSI) has developed standards for safeworkplace laser exposure based on the combination of theoretical andempirical data. The “maximum permissible exposure” (MPE) is the safetylevel, set at approximately 1/10^(th) of the laser exposure levelexpected to produce biological effects. At a laser exposure level of 1times MPE, absolute safety would be expected and retinal exposure tolaser radiation at this level would be expected to have no biologicaffect. Based on ANSI data, a 50% of some risk of suffering a barelyvisible (threshold) retinal burn is generally encountered at 10 timesMPE for conventional continuous wave laser exposure. For a low-dutycycle micropulsed laser exposure of the same power, the risk ofthreshold retinal burn is approximately 100 times MPE. Thus, thetherapeutic range—the interval of doing nothing at all and the 50% ofsome likelihood of producing a threshold retinal burn—for low-duty cyclemicropulsed laser irradiation is 10 times wider than for continuous wavelaser irradiation with the same energy. It has been determined that safeand effective subthreshold photocoagulation using a low-duty cyclemicropulsed diode laser is between 18 times and 55 times MPE, such aswith a preferred laser exposure to the retina at 47 times MPE for anear-infrared 810 nm diode laser. At this level, the inventor hasobserved that there is therapeutic effectiveness with no retinal damagewhatsoever.

It has been found that the intensity or power of a low-duty cycle 810 nmlaser beam between 100 watts to 590 watts per square centimeter iseffective yet safe. A particularly preferred intensity or power of thelaser light beam is approximately 250-350 watts per square centimeterfor an 810 nm micropulsed diode laser.

Power limitations in current micropulsed diode lasers require fairlylong exposure duration. The longer the laser exposure, the moreimportant the center-spot heat dissipating ability toward the unexposedtissue at the margins of the laser spot and toward the underlyingchoriocapillaris. Thus, the radiant beam of an 810 nm diode laser shouldhave an exposure envelope duration of 500 milliseconds or less, andpreferably approximately 100-300 milliseconds. Of course, if micropulseddiode lasers become more powerful, the exposure duration will belessened accordingly. It will be understood that the exposure envelopeduration is a duration of time where the micropulsed laser beam would beexposed to the same spot or location of the retina, although the actualtime of exposure of the tissue to the laser is much less as the laserlight pulse is less than a millisecond in duration, and typicallybetween 50 microseconds to 100 microseconds in duration.

Invisible phototherapy or true subthreshold photocoagulation inaccordance with the present invention can be performed at various laserlight wavelengths, such as from a range of 532 nm to 1300 nm. Use of adifferent wavelength can impact the preferred intensity or power of thelaser light beam and the exposure envelope duration in order that theretinal tissue is not damaged, yet therapeutic effect is achieved.

Another parameter of the present invention is the duty cycle (thefrequency of the train of micropulses, or the length of the thermalrelaxation time in between consecutive pulses). It has been found thatthe use of a 10% duty cycle or higher adjusted to deliver micropulsedlaser at similar irradiance at similar MPE levels significantly increasethe risk of lethal cell injury, particularly in darker fundi. However,duty cycles less than 10%, and preferably approximately 5% duty cycle orless have demonstrated adequate thermal rise and treatment at the levelof the RPE cell to stimulate a biologic response, but remained below thelevel expected to produce lethal cell injury, even in darkly pigmentedfundi. Moreover, if the duty cycle is less than 5%, the exposureenvelope duration in some instances can exceed 500 milliseconds.

In a particularly preferred embodiment, the use of small retinal laserspots is used. This is due to the fact that larger spots can contributeto uneven heat distribution and insufficient heat dissipation within thelarge retinal laser spot, potentially causing tissue damage or eventissue destruction towards the center of the larger laser spot. In thisusage, “small” would generally apply to retinal spots less than 3 mm indiameter. However, the smaller the retinal spot, the more ideal the heatdissipation and uniform energy application becomes. Thus, at the powerintensity and exposure duration described above, small spots, such as25-300 micrometers in diameter, or small geometric lines or otherobjects are preferred so as to maximize even heat distribution and heatdissipation to avoid tissue damage.

Thus, the following key parameters have been found in order to createharmless, “true” subthreshold photocoagulation in accordance with thepresent invention: a) a light beam having a wavelength of at least 532nm, and preferably between 532 nm to 1300 nm; b) a low duty cycle, suchas less than 10% (and preferably 5% or less); c) a small spot size tominimize heat accumulation and assure uniform heat distribution within agiven laser spot so as to maximize heat dissipation; d) sufficient powerto produce retinal laser exposures of between 18 times-55 times MPEproducing an RPE temperature rise of 7° C.-14° C.; and retinalirradiance of between 100-590 W/cm².

Using the foregoing parameters, a harmless yet therapeutically effective“true” subthreshold or invisible photocoagulation phototherapy treatmentcan be attained which has been found to produce the benefits ofconventional photocoagulation phototherapy, but avoid the drawbacks andcomplications of conventional phototherapy. In fact, “true” subthresholdphotocoagulation phototherapy in accordance with the present inventionenables the physician to apply a “low-intensity/high-density”phototherapy treatment, such as illustrated in FIG. 3B, and treat theentire retina, including sensitive areas such as the macula and even thefovea without creating visual loss or other damage. As indicated above,using conventional phototherapies, the entire retina, and particularlythe fovea, cannot be treated as it will create vision loss due to thetissue damage in sensitive areas.

Conventional retina-damaging laser treatment is limited in treatmentdensity, requiring subtotal treatment of the retina, including subtotaltreatment of the particular areas of retinal abnormality. However,recent studies demonstrate that eyes in diabetics may have diffuseretinal abnormalities without otherwise clinically visible diabeticretinopathy, and eyes with localized areas of clinically identifiableabnormality, such as diabetic macular edema or central serouschorioretinopathy, often have total retinal dysfunction detectable onlyby retinal function testing. The ability of the invention to harmlesslytreat the entire retina thus allows, for the first time, bothpreventative and therapeutic treatment of eyes with retinal diseasecompletely rather than locally or subtotally; and early treatment priorto the manifestation of clinical retinal disease and visual loss.

As discussed above, it is conventional thinking that tissue damage andlesions must be created in order to have a therapeutic effect. However,the inventor has found that this simply is not the case. In the absenceof laser-induced retinal damage, there is no loss of functional retinaltissue and no inflammatory response to treatment. Adverse treatmenteffects are thus completely eliminated and functional retina preservedrather than sacrificed. This may yield superior visual acuity resultscompared to conventional photocoagulation treatment.

The present invention spares the neurosensory retina and is selectivelyabsorbed by the RPE. Current theories of the pathogenesis of retinalvascular disease especially implicate cytokines, potent extra cellularvasoactive factors produced by the RPE, as important mediators ofretinal vascular disease. The present invention both selectively targetsand avoids lethal buildup within RPE. Thus, with the present inventionthe capacity for the treated RPE to participate in a therapeuticresponse is preserved and even enhanced rather than eliminated as aresult their destruction of the RPE in conventional photocoagulationtherapies.

It has been noted that the clinical effects of cytokines may follow a“U-shaped curve” where small physiologic changes in cytokine production,denoted by the left side of curve, may have large clinical effectscomparable to high-dose (pharmacologic) therapy (denoted by the rightside of the curve). Using sublethal laser exposures in accordance withthe present invention may be working on the left side of the curve wherethe treatment response may approximate more of an “on/off” phenomenonrather than a dose-response. This might explain the clinicaleffectiveness of the present invention observed at low reportedirradiances. This is also consistent with clinical experience andin-vitro studies of laser-tissue interaction, wherein increasingirradiance may simply increase the risk of thermal retinal damagewithout improving the therapeutic effect.

Another mechanism through which SDM might work is the activation of heatshock proteins (HSPs). Despite a near infinite variety of possiblecellular abnormalities, cells of all types share a common and highlyconserved mechanism of repair: heat shock proteins (HSPs). HSPs areelicited almost immediately, in seconds to minutes, by almost any typeof cell stress or injury. In the absence of lethal cell injury, HSPs areextremely effective at repairing and returning the viable cell toward amore normal functional state. Although HSPs are transient, generallypeaking in hours and persisting for a few days, their effects may belong lasting. HSPs reduce inflammation, a common factor in many retinaldisorders, including diabetic retinopathy (DR) and AMD.

Laser treatment induces HSP activation and, in the case of retinaltreatment, thus alters and normalizes retinal cytokine expression. Themore sudden and severe the non-lethal cellular stress (such as laserirradiation), the more rapid and robust HSP production. Thus, a burst ofrepetitive low temperature thermal spikes at a very steep rate of change(˜20° C. elevation with each 100 μs micropulse, or 20,000° C./sec)produced by each SDM exposure is especially effective in stimulatingproduction of HSPs, particularly compared to non-lethal exposure tosubthreshold treatment with continuous wave lasers, which can duplicateonly the low average tissue temperature rise.

Laser wavelengths below 532 nm produce increasingly cytotoxicphotochemical effects. At 532 nm-1300 nm, SDM produces photothermal,rather than photochemical, cellular stress. Thus, SDM is able to affectthe tissue, including RPE, without damaging it. Consistent with HSPactivation, SDM produces prompt clinical effects, such as rapid andsignificant improvement in retinal electrophysiology, visual acuity,contrast visual acuity and improved macular sensitivity measured bymicroperimetry, as well as long-term effects, such as reduction of DMEand involution of retinal neovascularization.

In the retina, the clinical benefits of SDM are thus produced bysub-morbid photothermal RPE HSP activation. In dysfunctional RPE cells,HSP stimulation by SDM results in normalized cytokine expression, andconsequently improved retinal structure and function. The therapeuticeffects of this “low-intensity” laser/tissue interaction are thenamplified by “high-density” laser application, recruiting all thedysfunctional RPE in the targeted area, thereby maximizing the treatmenteffect. These principles define the treatment strategy of SDM describedherein. The ability of SDM to produce therapeutic effects similar toboth drugs and photocoagulation indicates that laser-induced retinaldamage (for effects other than cautery) is unnecessary andnon-therapeutic; and, in fact, detrimental because of the loss ofretinal function and incitement of inflammation.

Because normally functioning cells are not in need of repair, HSPstimulation in normal cells would tend to have no notable clinicaleffect. The “patho-selectivity” of near infrared laser effects, such asSDM, affecting sick cells but not affecting normal ones, on various celltypes is consistent with clinical observations of SDM. This facility iskey to the suitability of SDM for early and preventative treatment ofeyes with chronic progressive disease and eyes with minimal retinalabnormality and minimal dysfunction. Finally, SDM has been reported tohave a clinically broad therapeutic range, unique among retinal lasermodalities, consistent with American National Standards Institute“Maximum Permissible Exposure” predictions. While SDM may cause directphotothermal effects such as entropic protein unfolding anddisaggregation, SDM appears optimized for clinically safe and effectivestimulation of HSP-mediated retinal repair.

With reference again to FIG. 3, the invisible, true subthresholdphotocoagulation phototherapy maximizes the therapeutic recruitment ofthe RPE through the concept of “maximize the affected surface area”, inthat all areas of RPE exposed to the laser irradiation are preserved,and available to contribute therapeutically. As discussed above withrespect to FIG. 2, it is believed that conventional therapy creates atherapeutic ring around the burned or damaged tissue areas, whereas thepresent invention creates a therapeutic area without any burned orotherwise destroyed tissue.

With reference now to FIGS. 4 and 5, spectral-domain OCT imaging isshown in FIG. 4 of the macular and foveal area of the retina beforetreatment with the present invention. FIG. 5 is of the optical coherencetomography (OCT) image of the same macula and fovea after treatmentusing the present invention, using a 131 micrometer retinal spot, 5%duty cycle, 0.3 second pulse duration, 0.9 watt peak power placedthroughout the area of macular thickening, including the fovea. It willbe noted that the enlarged dark area to the left of the fovea depression(representing the pathologic retinal thickening of diabetic macularedema) is absent, as well as the fact that there is an absence of anylaser-induced retinal damage. Such treatment simply would not beattainable with conventional techniques.

In another departure from conventional retinal photocoagulation, a lowred to infrared laser light beam, such as from an 810 nm micropulseddiode laser, is used instead of an argon laser. It has been found thatthe 810 nm diode laser is minimally absorbed and negligibly scattered byintraretinal blood, cataract, vitreous hemorrhage and even severelyedematous neurosensory retina. Differences in fundus coloration resultprimarily from differences in choroid pigmentation, and less ofvariation of the target RPE. Treatment in accordance with the presentinvention is thus simplified, requiring no adjustment in laserparameters for variations in macular thickening, intraretinalhemorrhage, and media opacity such as cataracts or fundus pigmentation,reducing the risk of error.

However, it is contemplated that the present invention could be utilizedwith micropulsed emissions of other wavelengths, such as the recentlyavailable 577 nm yellow and 532 nm green lasers, and others. The higherenergies and different tissue absorption characteristic of shorterwavelength lasers may increase retinal burn risk, effectively narrowingthe therapeutic window. In addition, the shorter wavelengths are morescattered by opaque ocular media, retinal hemorrhage and macular edema,potentially limiting usefulness and increasing the risk of retinaldamage in certain clinical settings. Thus, a low red to infrared laserlight beam is still preferred.

In fact, low power red and near-infrared laser exposure is known topositively affect many cell types, particularly normalizing the behaviorof cells and pathological environments, such as diabetes, through avariety of intracellular photo-acceptors. Cell function, in cytokineexpression, is normalized and inflammation reduced. By normalizingfunction of the viable RPE cells, the invention may induce changes inthe expression of multiple factors physiologically as opposed to drugtherapy that typically narrowly targets only a few post-cellular factorspharmacologically. The laser-induced physiologic alteration of RPEcytokine expression may account for the slower onset but long lastingbenefits using the present invention. Furthermore, use of aphysiologically invisible infrared or near-infrared laser wavelength,such as 750 nm-1300 nm, is perceived as comfortable by the patient, anddoes not cause reactive pupillary constriction, allowing visualizationof the ocular fundus and treatment of the retina to be performed withoutpharmacologic dilation of the patient pupil. This also eliminates thetemporary of visual disability typically lasting many hours followingpharmacologic pupillary dilation currently required for treatment withconventional laser photocoagulation. Currently, patient eye movement isa concern not only for creating the pattern of laser spots to treat theintended area, but also could result in exposure of conventional therapyto sensitive areas of the eye, such as the fovea, resulting in loss ofvision or other complications.

With reference now to FIG. 6, a schematic diagram is shown of a systemfor realizing the process of the present invention. The system,generally referred to by the reference number 30, includes a laserconsole 32, such as for example the 810 nm near infrared micropulseddiode laser in the preferred embodiment. The laser generates a laserlight beam which is passed through optics, such as an optical lens ormask, or a plurality of optical lenses and/or masks 34 as needed. Thelaser projector optics 34 pass the shaped light beam to a coaxialwide-field non-contact digital optical viewing system/camera 36 forprojecting the laser beam light onto the eye 38 of the patient. It willbe understood that the box labeled 36 can represent both the laser beamprojector as well as a viewing system/camera, which might in realitycomprise two different components in use. The viewing system/camera 36provides feedback to a display monitor 40, which may also include thenecessary computerized hardware, data input and controls, etc. formanipulating the laser 32, the optics 34, and/or the projection/viewingcomponents 36.

As discussed above, current treatment requires the application of alarge number of individual laser beam spots singly applied to the targettissue to be treated. These can number in the hundreds or even thousandsfor the desired treatment area. This is very time intensive andlaborious.

With reference now to FIG. 7, in one embodiment, the laser light beam 42is passed through a collimator lens 44 and then through a mask 46. In aparticularly preferred embodiment, the mask 46 comprises a diffractiongrating. The mask/diffraction grating 46 produces a geometric object, ormore typically a geometric pattern of simultaneously produced multiplelaser spots or other geometric objects. This is represented by themultiple laser light beams labeled with reference number 48.Alternatively, the multiple laser spots may be generated by a pluralityof fiber optic wires. Either method of generating laser spots allows forthe creation of a very large number of laser spots simultaneously over avery wide treatment field, such as consisting of the entire retina. Infact, a very high number of laser spots, perhaps numbering in thehundreds even thousands or more could cover the entire ocular fundus andentire retina, including the macula and fovea, retinal blood vessels andoptic nerve. The intent of the process in the present invention is tobetter ensure complete and total coverage and treatment, sparing none ofthe retina by the laser so as to improve vision.

Using optical features with a feature size on par with the wavelength ofthe laser employed, for example using a diffraction grating, it ispossible to take advantage of quantum mechanical effects which permitssimultaneous application of a very large number of laser spots for avery large target area. The individual spots produced by suchdiffraction gratings are all of a similar optical geometry to the inputbeam, with minimal power variation for each spot. The result is aplurality of laser spots with adequate irradiance to produce harmlessyet effective treatment application, simultaneously over a large targetarea. The present invention also contemplates the use of other geometricobjects and patterns generated by other diffractive optical elements.

The laser light passing through the mask 46 diffracts, producing aperiodic pattern a distance away from the mask 46, shown by the laserbeams labeled 48 in FIG. 7. The single laser beam 42 has thus beenformed into multiple, up to hundreds or even thousands, of individuallaser beams 48 so as to create the desired pattern of spots or othergeometric objects. These laser beams 48 may be passed through additionallenses, collimators, etc. 50 and 52 in order to convey the laser beamsand form the desired pattern on the patient's retina. Such additionallenses, collimators, etc. 50 and 52 can further transform and redirectthe laser beams 48 as needed.

Arbitrary patterns can be constructed by controlling the shape, spacingand pattern of the optical mask 46. The pattern and exposure spots canbe created and modified arbitrarily as desired according to applicationrequirements by experts in the field of optical engineering.Photolithographic techniques, especially those developed in the field ofsemiconductor manufacturing, can be used to create the simultaneousgeometric pattern of spots or other objects.

Although hundreds or even thousands of simultaneous laser spots could begenerated and created and formed into patterns to be applied to the eyetissue, due to the requirements of not overheating the eye tissue, andparticularly the eye lens, there are constraints on the number oftreatment spots or beams which can be simultaneously used in accordancewith the present invention. Each individual laser beam or spot requiresa minimum average power over a train duration to be effective. However,at the same time, eye tissue cannot exceed certain temperature riseswithout becoming damaged. For example, there is a 4° C. restriction onthe eye lens temperature rise which would set an upper limit on theaverage power that can be sent through the lens so as not to overheatand damage the lens of the eye. For example, using an 810 nm wavelengthlaser, the number of simultaneous spots generated and used could numberfrom as few as 1 and up to approximately 100 when a 0.04 (4%) duty cycleand a total train duration of 0.3 seconds (300 milliseconds) is used forpanretinal coverage. The water absorption increases as the wavelength isincreased, resulting in heating over the long path length through thevitreous humor in front of the retina. For shorter wavelengths, e.g.,577 nm, the absorption coefficient in the RPE's melanin can be higher,and therefore the laser power can be lower. For example, at 577 nm, thepower can be lowered by a factor of 4 for the invention to be effective.Accordingly, there can be as few as a single laser spot or up toapproximately 400 laser spots when using the 577 nm wavelength laserlight, while still not harming or damaging the eye.

The present invention can use a multitude of simultaneously generatedtherapeutic light beams or spots, such as numbering in the dozens oreven hundreds, as the parameters and methodology of the presentinvention create therapeutically effective yet non-destructive andnon-permanently damaging treatment, allowing the laser light spots to beapplied to any portion of the retina, including the fovea, whereasconventional techniques are not able to use a large number ofsimultaneous laser spots, and are often restricted to only one treatmentlaser beam, in order to avoid accidental exposure of sensitive areas ofthe retina, such as the fovea, as these will be damaged from theexposure to conventional laser beam methodologies, which could causeloss of eyesight and other complications.

FIG. 8 illustrates diagrammatically a system which couples multiplelight sources into the pattern-generating optical subassembly describedabove. Specifically, this system 30′ is similar to the system 30described in FIG. 6 above. The primary differences between the alternatesystem 30′ and the earlier described system 30 is the inclusion of aplurality of laser consoles 32, the outputs of which are each fed into afiber coupler 54. The fiber coupler produces a single output that ispassed into the laser projector optics 34 as described in the earliersystem. The coupling of the plurality of laser consoles 32 into a singleoptical fiber is achieved with a fiber coupler 54 as is known in theart. Other known mechanisms for combining multiple light sources areavailable and may be used to replace the fiber coupler described herein.

In this system 30′ the multiple light sources 32 follow a similar pathas described in the earlier system 30, i.e., collimated, diffracted,recollimated, and directed into the retina with a steering mechanism. Inthis alternate system 30′ the diffractive element must functiondifferently than described earlier depending upon the wavelength oflight passing through, which results in a slightly varying pattern. Thevariation is linear with the wavelength of the light source beingdiffracted. In general, the difference in the diffraction angles issmall enough that the different, overlapping patterns may be directedalong the same optical path through the steering mechanism 36 to theretina 38 for treatment. The slight difference in the diffraction angleswill affect how the steering pattern achieves coverage of the retina.

Since the resulting pattern will vary slightly for each wavelength, asequential offsetting to achieve complete coverage will be different foreach wavelength. This sequential offsetting can be accomplished in twomodes. In the first mode, all wavelengths of light are appliedsimultaneously without identical coverage. An offsetting steeringpattern to achieve complete coverage for one of the multiple wavelengthsis used. Thus, while the light of the selected wavelength achievescomplete coverage of the retina, the application of the otherwavelengths achieves either incomplete or overlapping coverage of theretina. The second mode sequentially applies each light source of avarying or different wavelength with the proper steering pattern toachieve complete coverage of the retina for that particular wavelength.This mode excludes the possibility of simultaneous treatment usingmultiple wavelengths, but allows the optical method to achieve identicalcoverage for each wavelength. This avoids either incomplete oroverlapping coverage for any of the optical wavelengths.

These modes may also be mixed and matched. For example, two wavelengthsmay be applied simultaneously with one wavelength achieving completecoverage and the other achieving incomplete or overlapping coverage,followed by a third wavelength applied sequentially and achievingcomplete coverage.

FIG. 9 illustrates diagrammatically yet another alternate embodiment ofthe inventive system 30″. This system 30″ is configured generally thesame as the system 30 depicted in FIG. 6. The main difference resides inthe inclusion of multiple pattern-generating subassembly channels tunedto a specific wavelength of the light source. Multiple laser consoles 32are arranged in parallel with each one leading directly into its ownlaser projector optics 34. The laser projector optics of each channel 58a, 58 b, 58 c comprise a collimator 44, mask or diffraction grating 48and recollimators 50, 52 as described in connection with FIG. 7above—the entire set of optics tuned for the specific wavelengthgenerated by the corresponding laser console 32. The output from eachset of optics 34 is then directed to a beam splitter 56 for combinationwith the other wavelengths. It is known by those skilled in the art thata beam splitter used in reverse can be used to combine multiple beams oflight into a single output.

The combined channel output from the final beam splitter 56 c is thendirected through the camera 36 which applies a steering mechanism toallow for complete coverage of the retina 38.

In this system 30″ the optical elements for each channel are tuned toproduce the exact specified pattern for that channel's wavelength.Consequently, when all channels are combined and properly aligned asingle steering pattern may be used to achieve complete coverage of theretina for all wavelengths.

The system 30″ may use as many channels 58 a, 58 b, 58 c, etc. and beamsplitters 56 a, 56 b, 56 c, etc. as there are wavelengths of light beingused in the treatment.

Implementation of the system 30″ may take advantage of differentsymmetries to reduce the number of alignment constraints. For example,the proposed grid patterns are periodic in two dimensions and steered intwo dimensions to achieve complete coverage. As a result, if thepatterns for each channel are identical as specified, the actual patternof each channel would not need to be aligned for the same steeringpattern to achieve complete coverage for all wavelengths. Each channelwould only need to be aligned optically to achieve an efficientcombination.

In system 30″, each channel begins with a light source 32, which couldbe from an optical fiber as in other embodiments of thepattern-generating subassembly. This light source 32 is directed to theoptical assembly 34 for collimation, diffraction, recollimation anddirected into the beam splitter which combines the channel with the mainoutput.

The field of photobiology reveals that different biologic effects may beachieved by exposing target tissues to lasers of different wavelengths.The same may also be achieved by consecutively applying multiple lasersof either different or the same wavelength in sequence with variabletime periods of separation and/or with different irradiant energies. Thepresent invention anticipates the use of multiple laser, light orradiant wavelengths (or modes) applied simultaneously or in sequence tomaximize or customize the desired treatment effects. This method alsominimizes potential detrimental effects. The optical methods and systemsillustrated and described above provide simultaneous or sequentialapplication of multiple wavelengths.

Typically, the system of the present invention incorporates a guidancesystem to ensure complete and total retinal treatment with retinalphotostimulation. This guidance system is to be distinguished fromtraditional retinal laser guidance systems that are employed to bothdirect treatment to a specific retinal location; and to direct treatmentaway from sensitive locations such as the fovea that would be damaged byconventional laser treatment, as the treatment method of the presentinvention is harmless, the entire retina, including the fovea and evenoptical nerve, can be treated. Moreover, protection against accidentalvisual loss by accidental patient movement is not a concern. Instead,patient movement would mainly affect the guidance in tracking of theapplication of the laser light to ensure adequate coverage.Fixation/tracking/registration systems consisting of a fixation target,tracking mechanism, and linked to system operation are common in manyophthalmic diagnostic systems and can be incorporated into the presentinvention.

In a particularly preferred embodiment, the geometric pattern ofsimultaneous laser spots is sequentially offset so as to achieveconfluent and complete treatment of the retinal surface. Although asegment of the retina can be treated in accordance with the presentinvention, more ideally the entire retina will be treated within onetreatment session. This is done in a time-saving manner by placing aplurality of spots over the entire ocular fundus at once. This patternof simultaneous spots is scanned, shifted, or redirected as an entirearray sequentially, so as to cover the entire retina in a singletreatment session.

This can be done in a controlled manner using an optical scanningmechanism 60. FIGS. 10 and 11 illustrate an optical scanning mechanism60 which may be used in the form of a MEMS mirror, having a base 62 withelectronically actuated controllers 64 and 66 which serve to tilt andpan the mirror 68 as electricity is applied and removed thereto.Applying electricity to the controller 64 and 66 causes the mirror 68 tomove, and thus the simultaneous pattern of laser spots or othergeometric objects reflected thereon to move accordingly on the retina ofthe patient. This can be done, for example, in an automated fashionusing an electronic software program to adjust the optical scanningmechanism 60 until complete coverage of the retina, or at least theportion of the retina desired to be treated, is exposed to thephototherapy. The optical scanning mechanism may also be a small beamdiameter scanning galvo mirror system, or similar system, such as thatdistributed by Thorlabs. Such a system is capable of scanning the lasersin the desired offsetting pattern.

Since the parameters of the present invention dictate that the appliedradiant energy or laser light is not destructive or damaging, thegeometric pattern of laser spots, for example, can be overlapped withoutdestroying the tissue or creating any permanent damage. However, in aparticularly preferred embodiment, as illustrated in FIG. 12, thepattern of spots are offset at each exposure so as to create spacebetween the immediately previous exposure to allow heat dissipation andprevent the possibility of heat damage or tissue destruction. Thus, asillustrated in FIG. 12, the pattern, illustrated for exemplary purposesas a grid of sixteen spots, is offset each exposure such that the laserspots occupy a different space than previous exposures. It will beunderstood that the diagrammatic use of circles or empty dots as well asfilled dots are for diagrammatic purposes only to illustrate previousand subsequent exposures of the pattern of spots to the area, inaccordance with the present invention. The spacing of the laser spotsprevents overheating and damage to the tissue. It will be understoodthat this occurs until the entire retina, the preferred methodology, hasreceived phototherapy, or until the desired effect is attained. This canbe done, for example, by a scanning mechanism, such as by applyingelectrostatic torque to a micromachined mirror, as illustrated in FIGS.10 and 11. By combining the use of small retina laser spots separated byexposure free areas, prevents heat accumulation, and grids with a largenumber of spots per side, it is possible to atraumatically and invisiblytreat large target areas with short exposure durations far more rapidlythan is possible with current technologies. In this manner, alow-density treatment, such as illustrated in FIG. 3A, can become ahigh-density treatment, as illustrated in FIG. 3B.

By rapidly and sequentially repeating redirection or offsetting of theentire simultaneously applied grid array of spots or geometric objects,complete coverage of the target, such as a human retina, can be achievedrapidly without thermal tissue injury. This offsetting can be determinedalgorithmically to ensure the fastest treatment time and least risk ofdamage due to thermal tissue, depending on laser parameters and desiredapplication. The following has been modeled using the FraunhofferApproximation. With a mask having a nine by nine square lattice, with anaperture radius 9 μm, an aperture spacing of 600 μm, using a 890 nmwavelength laser, with a mask-lens separation of 75 mm, and secondarymask size of 2.5 mm by 2.5 mm, the following parameters will yield agrid having nineteen spots per side separated by 133 μm with a spot sizeradius of 6 μm. The number of exposures “m” required to treat (coverconfluently with small spot applications) given desired area side-length“A”, given output pattern spots per square side “n”, separation betweenspots “R”, spot radius “r” and desired square side length to treat area“A”, can be given by the following formula:

$m = {\frac{A}{nR}{{floor}\left( \frac{R}{2r} \right)}^{2}}$

With the foregoing setup, one can calculate the number of operations mneeded to treat different field areas of exposure. For example, a 3 mm×3mm area, which is useful for treatments, would require 98 offsettingoperations, requiring a treatment time of approximately thirty seconds.Another example would be a 3 cm×3 cm area, representing the entire humanretinal surface. For such a large treatment area, a much largersecondary mask size of 25 mm by 25 mm could be used, yielding atreatment grid of 190 spots per side separated by 133 μm with a spotsize radius of 6 μm. Since the secondary mask size was increased by thesame factor as the desired treatment area, the number of offsettingoperations of approximately 98, and thus treatment time of approximatelythirty seconds, is constant. These treatment times represent at leastten to thirty times reduction in treatment times compared to currentmethods of sequential individual laser spot applications. Field sizes of3 mm would, for example, allow treatment of the entire human macula in asingle exposure, useful for treatment of common blinding conditions suchas diabetic macular edema and age-related macular degeneration.Performing the entire 98 sequential offsettings would ensure entirecoverage of the macula.

Of course, the number and size of retinal spots produced in asimultaneous pattern array can be easily and highly varied such that thenumber of sequential offsetting operations required to completetreatment can be easily adjusted depending on the therapeuticrequirements of the given application.

Furthermore, by virtue of the small apertures employed in thediffraction grating or mask, quantum mechanical behavior may be observedwhich allows for arbitrary distribution of the laser input energy. Thiswould allow for the generation of any arbitrary geometric shapes orpatterns, such as a plurality of spots in grid pattern, lines, or anyother desired pattern. Other methods of generating geometric shapes orpatterns, such as using multiple fiber optical fibers or microlenses,could also be used in the present invention. Time savings from the useof simultaneous projection of geometric shapes or patterns permits thetreatment fields of novel size, such as the 1.2 cm^2 area to accomplishwhole-retinal treatment, in a single clinical setting or treatmentsession.

With reference now to FIGS. 13 and 14, instead of a geometric pattern ofsmall laser spots, the present invention contemplates use of othergeometric objects or patterns. For example, a single line 70 of laserlight, formed by the continuously or by means of a series of closelyspaced spots, can be created. An offsetting optical scanning mechanismcan be used to sequentially scan the line over an area, illustrated bythe downward arrow in FIG. 13. With reference now to FIG. 14, the samegeometric object of a line 70 can be rotated, as illustrated by thearrows, so as to create a circular field of phototherapy. The potentialnegative of this approach, however, is that the central area will berepeatedly exposed, and could reach unacceptable temperatures. Thiscould be overcome, however, by increasing the time between exposures, orcreating a gap in the line such that the central area is not exposed.

Power limitations in current micropulsed diode lasers require fairlylong exposure duration. The longer the exposure, the more important thecenter-spot heat dissipating ability toward the unexposed tissue at themargins of the laser spot and toward the underlying choriocapillaris asin the retina. Thus, the micropulsed laser light beam of an 810 nm diodelaser should have an exposure envelope duration of 500 milliseconds orless, and preferably approximately 300 milliseconds. Of course, ifmicropulsed diode lasers become more powerful, the exposure durationshould be lessened accordingly.

Aside from power limitations, another parameter of the present inventionis the duty cycle, or the frequency of the train of micropulses, or thelength of the thermal relaxation time between consecutive pulses. It hasbeen found that the use of a 10% duty cycle or higher adjusted todeliver micropulsed laser at similar irradiance at similar MPE levelssignificantly increase the risk of lethal cell injury, particularly indarker fundi. However, duty cycles of less than 10%, and preferably 5%or less demonstrate adequate thermal rise and treatment at the level ofthe MPE cell to stimulate a biological response, but remain below thelevel expected to produce lethal cell injury, even in darkly pigmentedfundi. The lower the duty cycle, however, the exposure envelope durationincreases, and in some instances can exceed 500 milliseconds.

Each micropulse lasts a fraction of a millisecond, typically between 50microseconds to 100 microseconds in duration. Thus, for the exposureenvelope duration of 300-500 milliseconds, and at a duty cycle of lessthan 5%, there is a significant amount of wasted time betweenmicropulses to allow the thermal relaxation time between consecutivepulses. Typically, a delay of between 1 and 3 milliseconds, andpreferably approximately 2 milliseconds, of thermal relaxation time isneeded between consecutive pulses. For adequate treatment, the retinalcells are typically exposed or hit by the laser light between 50-200times, and preferably between 75-150 at each location. With the 1-3milliseconds of relaxation or interval time, the total time inaccordance with the embodiments described above to treat a given area,or more particularly the locations on the retina which are being exposedto the laser spots is between 200 milliseconds and 500 milliseconds onaverage. The thermal relaxation time is required so as not to overheatthe cells within that location or spot and so as to prevent the cellsfrom being damaged or destroyed. While time periods of 200-500milliseconds do not seem long, given the small size of the laser spotsand the need to treat a relatively large area of the retina, treatingthe entire macula or the entire retina can take a significant amount oftime, particularly from the perspective of a patient who is undergoingtreatment.

Accordingly, the present invention in a particularly preferredembodiment utilizes the interval between consecutive laser lightapplications to the same location (typically between 1 to 3milliseconds) to apply the laser light to a second treatment area, oradditional areas, of the retina and/or fovea that is spaced apart fromthe first treatment area. The laser beams are returned to the firsttreatment location, or previous treatment locations, within thepredetermined interval of time so as to provide sufficient thermalrelaxation time between consecutive pulses, yet also sufficiently treatthe cells in those locations or areas properly by sufficientlyincreasing the temperature of those cells over time by repeatedlyapplying the laser light to that location in order to achieve thedesired therapeutic benefits of the invention.

It is important to return to a previously treated location within 1-3milliseconds, and preferably approximately 2 milliseconds, to allow thearea to cool down sufficiently during that time, but also to treat itwithin the necessary window of time. For example, one cannot wait one ortwo seconds and then return to a previously treated area that has notyet received the full treatment necessary, as the treatment will not beas effective or perhaps not effective at all. However, during thatinterval of time, typically approximately 2 milliseconds, at least oneother area, and typically multiple areas, can be treated with a laserlight application as the laser light pulses are typically 50 seconds to100 microseconds in duration. The number of additional areas which canbe treated is limited only by the micropulse duration and the ability tocontrollably move the laser light beams from one area to another.Currently, approximately four additional areas which are sufficientlyspaced apart from one another can be treated during the thermalrelaxation intervals beginning with a first treatment area. Thus,multiple areas can be treated, at least partially, during the 200-500millisecond exposure envelope for the first area. Thus, in a singleinterval of time, instead of only 100 simultaneous light spots beingapplied to a treatment area, approximately 500 light spots can beapplied during that interval of time in different treatment areas. Thiswould be the case, for example, for a laser light beam having awavelength of 810 nm. For shorter wavelengths, such as 570 nm, even agreater number of individual locations can be exposed to the laser beamsto create light spots. Thus, instead of a maximum of approximately 400simultaneous spots, approximately 2,000 spots could be covered duringthe interval between micropulse treatments to a given area or location.

As mentioned above, typically each location has between 50-200, and moretypically between 75-150, light applications applied thereto over thecourse of the exposure envelope duration (typically 200-500milliseconds) to achieve the desired treatment. In accordance with anembodiment of the present invention, the laser light would be reappliedto previously treated areas in sequence during the relaxation timeintervals for each area or location. This would occur repeatedly until apredetermined number of laser light applications to each area to betreated have been achieved.

This is diagrammatically illustrated in FIGS. 15A-15D. FIG. 15Aillustrates with solid circles a first area having laser light appliedthereto as a first application. The laser beams are offset ormicroshifted to a second exposure area, followed by a third exposurearea and a fourth exposure area, as illustrated in FIG. 15B, until thelocations in the first exposure area need to be retreated by havinglaser light applied thereto again within the thermal relaxation timeinterval. The locations within the first exposure area would then havelaser light reapplied thereto, as illustrated in FIG. 15C. Secondary orsubsequent exposures would occur in each exposure area, as illustratedin FIG. 15D by the increasingly shaded dots or circles until the desirednumber of exposures or hits or light applications had been achieved totherapeutically treat these areas, diagrammatically illustrated by theblackened circles in exposure area 1 in FIG. 15D. When a first orprevious exposure area has been completed treated, this enables thesystem to add an additional exposure area, which process is repeateduntil the entire area of retina to be treated has been fully treated. Itshould be understood that the use of solid circles, broken line circles,partially shaded circles, and fully shaded circles are for explanatorypurposes only, as in fact the exposure of the laser light in accordancewith the present invention is invisible and non-detectable to both thehuman eye as well as known detection devices and techniques.

Adjacent exposure areas must be separated by at least a predeterminedminimum distance to avoid thermal tissue damage. Such distance is atleast 0.5 diameter away from the immediately preceding treated locationor area, and more preferably between 1-2 diameters away. Such spacingrelates to the actually treated locations in a previous exposure area.It is contemplated by the present invention that a relatively large areamay actually include multiple exposure areas therein which are offset ina different manner than that illustrated in FIG. 15. For example, theexposure areas could comprise the thin lines illustrated in FIGS. 13 and14, which would be repeatedly exposed in sequence until all of thenecessary areas were fully exposed and treated. In accordance with thepresent invention, this can comprise a limited area of the retina, theentire macula or panmacular treatment, or the entire retina, includingthe fovea. However, due to the methodology of the present invention, thetime required to treat that area of the retina to be treated or theentire retina is significantly reduced, such as by a factor of 4 or 5times, such that a single treatment session takes much less time for themedical provider and the patient need not be in discomfort for as longof a period of time.

In accordance with this embodiment of the invention of applying one ormore treatment beams to the retina at once, and moving the treatmentbeams to a series of new locations, then bringing the beams back toretreat the same location or area repeatedly has been found to alsorequire less power compared to the methodology of keeping the laserbeams in the same locations or area during the entire exposure envelopeduration. With reference to FIGS. 16-18, there is a linear relationshipbetween the pulse length and the power necessary, but there is alogarithmic relationship between the heat generated.

With reference to FIG. 16, a graph is provided wherein the x-axisrepresents the Log of the average power in watts and the y-axisrepresents the treatment time, in seconds. The lower curve is forpanmacular treatment and the upper curve is for panretinal treatment.This would be for a laser light beam having a micropulse time of 50microseconds, a period of 2 milliseconds period of time between pulses,and duration of train on a spot of 300 milliseconds. The areas of eachretinal spot are 100 microns, and the laser power for these 100 micronretinal spots is 0.74 watts. The panmacular area is 0.55 CM², requiring7,000 panmacular spots total, and the panretinal area is 3.30 CM²,requiring 42,000 laser spots for full coverage. Each RPE spot requires aminimum energy in order for its reset mechanism to be adequatelyactivated, in accordance with the present invention, namely, 38.85joules for panmacular and 233.1 joules for panretinal. As would beexpected, the shorter the treatment time, the larger the requiredaverage power. However, there is an upper limit on the allowable averagepower, which limits how short the treatment time can be.

As mentioned above, there are not only power constraints with respect tothe laser light available and used, but also the amount of power thatcan be applied to the eye without damaging eye tissue. For example,temperature rise in the lens of the eye is limited, such as between 4°C. so as not to overheat and damage the lens, such as causing cataracts.Thus, an average power of 7.52 watts could elevate the lens temperatureto approximately 4° C. This limitation in power increases the minimumtreatment time.

However, with reference to FIG. 17, the total power per pulse requiredis less in the microshift case of repeatedly and sequentially moving thelaser spots and returning to prior treated locations, so that the totalenergy delivered and the total average power during the treatment timeis the same. FIGS. 17 and 18 show how the total power depends ontreatment time. This is displayed in FIG. 17 for panmacular treatment,and in FIG. 18 for panretinal treatment. The upper, solid line or curverepresents the embodiment where there are no microshifts takingadvantage of the thermal relaxation time interval, such as described andillustrated in FIG. 12, whereas the lower dashed line represents thesituation for such microshifts, as described and illustrated in FIG. 15.FIGS. 17 and 18 show that for a given treatment time, the peak totalpower is less with microshifts than without microshifts. This means thatless power is required for a given treatment time using themicroshifting embodiment of the present invention. Alternatively, theallowable peak power can be advantageously used, reducing the overalltreatment time.

Thus, in accordance with FIGS. 16-18, a log power of 1.0 (10 watts)would require a total treatment time of 20 seconds using themicroshifting embodiment of the present invention, as described herein.It would take more than 2 minutes of time without the microshifts, andinstead leaving the micropulsed light beams in the same location or areaduring the entire treatment envelope duration. There is a minimumtreatment time according to the wattage. However, this treatment timewith microshifting is much less than without microshifting. As the laserpower required is much less with the microshifting, it is possible toincrease the power in some instances in order to reduce the treatmenttime for a given desired retinal treatment area. The product of thetreatment time and the average power is fixed for a given treatment areain order to achieve the therapeutic treatment in accordance with thepresent invention. This could be implemented, for example, by applying ahigher number of therapeutic laser light beams or spots simultaneouslyat a reduced power. Of course, since the parameters of the laser lightare selected to be therapeutically effective yet not destructive orpermanently damaging to the cells, no guidance or tracking beams arerequired, only the treatment beams as all areas of the retina, includingthe fovea, can be treated in accordance with the present invention. Infact, in a particularly preferred embodiment, the entire retina,including the fovea, is treated in accordance with the presentinvention, which is simply not possible using conventional techniques.

Although the present invention is described for use in connection with amicropulsed laser, theoretically a continuous wave laser couldpotentially be used instead of a micropulsed laser. However, with thecontinuous wave laser, there is concern of overheating as the laser ismoved from location to location in that the laser does not stop andthere could be heat leakage and overheating between treatment areas.Thus, while it is theoretically possible to use a continuous wave laser,in practice it is not ideal and the micropulsed laser is preferred.

Due to the unique characteristics of the present invention, allowing asingle set of optimized laser parameters, which are not significantlyinfluenced by media opacity, retinal thickening, or fundus pigmentation,a simplified user interface is permitted. While the operating controlscould be presented and function in many different ways, the systempermits a very simplified user interface that might employ only twocontrol functions. That is, an “activate” button, wherein a singledepression of this button while in “standby” would actuate and initiatetreatment. A depression of this button during treatment would allow forpremature halting of the treatment, and a return to “standby” mode. Theactivity of the machine could be identified and displayed, such as by anLED adjacent to or within the button. A second controlled function couldbe a “field size” knob. A single depression of this button could programthe unit to produce, for example, a 3 mm focal or a “macular” fieldspot. A second depression of this knob could program the unit to producea 6 mm or “posterior pole” spot. A third depression of this knob couldprogram the unit to produce a “pan retinal” or approximately 160°-220°panoramic retinal spot or coverage area. Manual turning of this knobcould produce various spot field sizes therebetween. Within each fieldsize, the density and intensity of treatment would be identical.Variation of the field size would be produced by optical or mechanicalmasking or apertures, such as the iris or LCD apertures described below.

Fixation software could monitor the displayed image of the ocularfundus. Prior to initiating treatment of a fundus landmark, such as theoptic nerve, or any part or feature of either eye of the patient(assuming orthophoria), could be marked by the operator on the displayscreen. Treatment could be initiated and the software would monitor thefundus image or any other image-registered to any part of either eye ofthe patient (assuming orthophoria) to ensure adequate fixation. A breakin fixation would automatically interrupt treatment. A break in fixationcould be detected optically; or by interruption of low energy infraredbeams projected parallel to and at the outer margins of the treatmentbeam by the edge of the pupil. Treatment would automatically resumetoward completion as soon as fixation was established. At the conclusionof treatment, determined by completion of confluent delivery of thedesired laser energy to the target, the unit would automaticallyterminate exposure and default to the “on” or “standby” mode. Due tounique properties of this treatment, fixation interruption would notcause harm or risk patient injury, but only prolong the treatmentsession.

The laser could be projected via a wide field non-contact lens to theocular fundus. Customized direction of the laser fields or particulartarget or area of the ocular fundus other than the central area could beaccomplished by an operator joy stick or eccentric patient gaze. Thelaser delivery optics could be coupled coaxially to a wide fieldnon-contact digital ocular fundus viewing system. The image of theocular fundus produced could be displayed on a video monitor visible tothe laser operator. Maintenance of a clear and focused image of theocular fundus could be facilitated by a joy stick on the camera assemblymanually directed by the operator. Alternatively, addition of a targetregistration and tracking system to the camera software would result ina completely automated treatment system.

A fixation image could be coaxially displayed to the patient tofacilitate ocular alignment. This image would change in shape and size,color, intensity, blink or oscillation rate or other regular orcontinuous modification during treatment to avoid photoreceptorexhaustion, patient fatigue and facilitate good fixation.

In addition, the results or images from other retinal diagnosticmodalities, such as OCT, retinal angiography, or autofluoresencephotography, might be displayed in parallel or by superimposition on thedisplay image of the patient's fundus to guide, aid or otherwisefacilitate the treatment. This parallel or superimposition of images canfacilitate identification of disease, injury or scar tissue on theretina.

The invention described herein is generally safe for panretinal and/ortrans-foveal treatment. However, it is possible that a user, i.e.,surgeon, preparing to limit treatment to a particular area of the retinawhere disease markers are located or to prevent treatment in aparticular area with darker pigmentation, such as from scar tissue. Inthis case, the camera 36 may be fitted with an iris aperture 72configured to selectively widen or narrow the opening through which thelight is directed into the eye 38 of the patient. FIG. 19 illustrates anopening 74 on a camera 36 fitted with such an iris aperture 72.Alternatively, the iris aperture 72 may be replaced or supplemented by aliquid crystal display (LCD) 76. The LCD 76 acts as a dynamic apertureby allowing each pixel in the display to either transmit or block thelight passing through it. Such an LCD 76 is depicted in FIG. 20.

Preferably, any one of the inventive systems 30, 30′, 30″ includes adisplay on a user interface with a live image of the retina as seenthrough the camera 36. The user interface may include an overlay of thislive image of the retina to select areas where the treatment light willbe limited or excluded by the iris aperture 72 and/or the LCD 76. Theuser may draw an outline on the live image as on a touch screen and thenselect for either the inside or the outside of that outline to havelimited or excluded coverage.

By way of example, if the user identifies scar tissue on the retina thatshould be excluded from treatment, the user would draw an outline aroundthe scar tissue and then mark the interior of that outline for exclusionfrom the laser treatment. The control system and user interface wouldthen send the proper control signal to the LCD 76 to block the projectedtreatment light through the pixels over the selected scar tissue. TheLCD 76 provides an added benefit of being useful for attenuating regionsof the projected pattern. This feature may be used to limit the peakpower output of certain spots within the pattern. Limiting the peakpower of certain spots in the pattern with the highest power output canbe used to make the treatment power more uniform across the retina.

Alternatively, the surgeon may use the fundus monitor to outline an areaof the retina to be treated or avoided; and the designated area thentreated or avoided by software directing the treatment beams to treat oravoid said areas without need or use of an obstructing LCD 76 diaphragm.

The inventors have found that treatment in accordance with the inventionof patients suffering from age-related macular degeneration (AMD) canslow the progress or even stop the progression of AMD. Further evidenceof this restorative treatment effect is the inventor's finding thattreatment can uniquely reduce the risk of vision loss in AMD due tochoroidal neovascularization by 80%. Most of the patients have seensignificant improvement in dynamic functional log MAR visual acuity andcontrast visual acuity after the treatment in accordance with theinvention, with some experiencing better vision. It is believed thatthis works by targeting, preserving, and “normalizing” (moving towardnormal) function of the retinal pigment epithelium (RPE).

Treatment in accordance with the invention has also been shown to stopor reverse the manifestations of the diabetic retinopathy disease statewithout treatment-associated damage or adverse effects, despite thepersistence of systemic diabetes mellitus. Studies published by theinventor have shown that the restorative effect of treatment canuniquely reduce the risk of progression of diabetic retinopathy by 85%.On this basis it is hypothesized that the invention might work byinducing a return to more normal cell function and cytokine expressionin diabetes-affected RPE cells, analogous to hitting the “reset” buttonof an electronic device to restore the factory default settings.

Based on the above information and studies, SDM treatment may directlyaffect cytokine expression and heat shock protein (HSP) activation inthe targeted tissue, particularly the retinal pigment epithelium (RPE)layer. Panretinal and panmacular SDM has been noted by the inventors toreduce the rate of progression of many retinal diseases, includingsevere non-proliferative and proliferative diabetic retinopathy, AMD,DME, etc. The known therapeutic treatment benefits of individuals havingthese retinal diseases, coupled with the absence of known adversetreatment effects, allows for consideration of early and preventativetreatment, liberal application and retreatment as necessary. The resettheory also suggests that the invention may have application to manydifferent types of RPE-mediated retinal disorders. In fact, the inventorhas recently shown that panmacular treatment can significantly improveretinal function and health, retinal sensitivity, and dynamic log MARvisual acuity and contrast visual acuity in dry age-related maculardegeneration, retinitis pigmentosa, cone-rod retinal degenerations, andStargardt's disease where no other treatment has previously been foundto do so.

Currently, retinal imaging and visual acuity testing guide management ofchronic, progressive retinal diseases. As tissue and/or organ structuraldamage and vision loss are late disease manifestations, treatmentinstituted at this point must be intensive, often prolonged andexpensive, and frequently fails to improve visual acuity and rarelyrestores normal vision. As the invention has been shown to be aneffective treatment for a number of retinal disorders without adversetreatment effects, and by virtue of its safety and effectiveness, it canalso be used to treat an eye to stop or delay the onset or symptoms ofretinal diseases prophylactically or as a preventative treatment forsuch retinal diseases. Any treatment that improves retinal function, andthus health, should also reduce disease severity, progression, untowardevents and visual loss. By beginning treatment early, prior topathologic structural change, and maintaining the treatment benefit byregular functionally-guided re-treatment, structural degeneration andvisual loss might thus be delayed if not prevented. Even modest earlyreductions in the rate of disease progression may lead to significantlong-term reductions and complications in visual loss. By mitigating theconsequences of the primary defect, the course of disease may be muted,progression slowed, and complications and visual loss reduced. This isreflected in the inventor's studies, finding that treatment reduces therisk of progression and visual loss in diabetic retinopathy by 85% andAMD by 80%.

In accordance with an embodiment of the present invention, it isdetermined that a patient, and more particularly an eye of the patient,has a risk for a retinal disease. This may be before retinal imagingabnormalities are detectable. Such a determination may be accomplishedby ascertaining if the patient is at risk for a chronic progressiveretinopathy, including diabetes, a risk for age-related maculardegeneration or retinitis pigmentosa. Alternatively, or additionally,results of a retinal examination or retinal test of the patient may beabnormal. A specific test, such as a retinal physiology test or agenetic test, may be conducted to establish that the patient has a riskfor a retinal disease.

A laser light beam, that is sublethal and creates true subthresholdphotocoagulation and retinal tissue, is generated and at least a portionof the retinal tissue is exposed to the generated laser light beamwithout damaging the exposed retinal or foveal tissue, so as to providepreventative and protective treatment of the retinal tissue of the eye.The treated retina may comprise the fovea, foveola, retinal pigmentepithelium (RPE), choroid, choroidal neovascular membrane, subretinalfluid, macula, macular edema, parafovea, and/or perifovea. The laserlight beam may be exposed to only a portion of the retina, orsubstantially the entire retina and fovea.

While most treatment effects appear to be long-lasting, if notpermanent, clinical observations suggest that it can appear to wear offon occasion. Accordingly, the retina is periodically retreated. This maybe done according to a set schedule or when it is determined that theretina of the patient is to be retreated, such as by periodicallymonitoring visual and/or retinal function or condition of the patient.

Although the present invention is particularly suited for treatment ofretinal diseases, such as diabetic retinopathy and macular edema, it hasbeen found that it can be used for other diseases as well. The systemand process of the present invention could target the trabecular meshwork as treatment for glaucoma, accomplished by another customizedtreatment field template. Moreover, treatment of retinal tissue usingSDM, as explained above, in eyes with advanced open-angle glaucoma haveshown improved key measures of optic nerve and ganglion cell function,indicating a significant neuroprotective effect of this treatment.Visual fields also improved, and there was no adverse treatment effects.Thus, it is believed that SDM, in accordance with the present invention,may aid in the clinical management of glaucoma by reducing the risk ofvisual loss, independent of intraocular pressure (IOP) lowering.

Low-intensity/high density subthreshold (sublethal) diode micropulselaser (SDM), as explained in detail above, has been shown to beeffective in the treatment of traditional retinal laser indications suchas diabetic macular edema, proliferative diabetic retinopathy, centralserious chorioretinopathy, and branch retinal vein occlusion, withoutadverse treatment effects. As described above, the mechanism of theretinal laser treatment is sometimes referred to herein as “reset todefault” theory, which postulates that the primary mode of retinal laseraction is sublethal activation of the retinal pigment epithelial (RPE)heat shock proteins. A study recently conducted also shows that SDMshould be neuroprotective in open-angle glaucoma.

Twenty-two patients (forty-three eyes total) were identified as eligiblefor the study, having glaucomatous optic nerve cupping and/or visualfield loss prior to SDM treatment, in accordance with the presentinvention. Under minimum slit-lamp illumination, the entire posteriorretina, including the fovea, circumscribed by the major vascular arcadeswas “painted” with 1500-2000 confluent spot applications of laser lighthaving parameters of 810 nm wavelength, 200 UM aerial spot size, 5% dutycycle, 1.4-watt power and 0.15 second duration. IOPs range 6-23 mm Hg(average 13) on 0-3 (average 1.3) topical medications. None of thepatients use systemic glaucoma medication. Preoperative Snellen visualacuity (VA) range 20/15 to counting fingers with a median of 20/52.

There were no observed adverse treatment effects. Snellen VAs and IOPswere unchanged after treatment. In addition to visually evoked potential(VEP) testing before and after SDM treatment, the eyes were evaluatedprior to treatment by clinical examinations, fundus photography,intravenous fundus fluorescein angiography, spectral-domain opticalcoherence tomography (OCT), pattern electroretinography (PERG), andOmnifield resolution perimetry (ORP). PERG, VEP, and ORP were performedone week prior to, and within one month after SDM treatment.

VEP was performed using an office-based commercially available system(Diopsys™ NOVA-TR, Diopsys, Inc., Pine Brook, New jersey, USA) approvedby the FDA for research and clinical use. Testing was performedaccording to manufacturer guidelines (www.diopsys.com). Gold active,ground, and reference electrodes (1 cm cup) were used to record the VEP.Following skin cleaning and abrasion, conductive gel was used to adherethe electrodes to the scalp. All subjects were refracted prior totesting and corrected for the 1-meter testing distance with a trialframe. VEP amplitude, latency, and alpha-wave activity (8-13 Hz) fromthe primary visual cortex were measured using one Grass goldactive-channel electrode, one reference electrode, and one groundelectrode placed according to manufacturer recommendations followingconfirmation of adequate testing impedence. An elastic headband was usedto maintain electrode position on the scalp. Subjects then placed theirhead in a chinrest/headrest and instructed to gaze at the center of themonitor at eye level and centered along the midline. The VEPmeasurements were recorded binocularly in a darkened room, undilated.

PERG was performed using standard protocols of a commercially availablesystem (Diopsys® Nova-ERG, Diopsys Corp., Pine Brook, New jersey)according to International Society for Clinical Electrophysiology ofVision guidelines. Both eyes were tested simultaneously and recordedindividually, undilated, and refracted for the 60 cm testing distance.For all visual stimuli, a luminance pattern occupying a 25° visual fieldis presented with a luminance reversal rate of 15 Hz.

The PERG “Concentric Ring” (CR) visual stimulus optimized for analyzingperipheral retinal sensitivity was employed, presenting with a circle ofone luminance and an outer ring with the contrasting luminance. Theconcentric ring stimulus used two sub-classes of stimuli with an innercircle occupying a visual field of 16° and 24°, respectively. Theconcentric ring stimuli used a mean luminance of 117.6 cd/m² with acontrast of 100%.

Patient and equipment preparation were carried out according to Diopsys™guidelines. Signal acquisition and analysis followed a standard glaucomascreening protocol. Test indices available for analysis included“Magnitude D”, “Magnitude (μV)”, and the “MagD(μV)/Mag(μV)” ratio.“Magnitude D” [MagD(μV)] is the frequency response of the time-domainaveraged signal in microvolts (μV). Inner retinal and/or ganglion celldysfunction cause signal latencies resulting in magnitude and phasevariability that reduce MagD(μV) by phase cancellation. Magnitude (μV)[Mag(μV)] measures the frequency response of the total signal inmicrovolts (μV). Mag (μV) reflects the signal strength and electrodeimpedance of the individual test sessions, as well as a gross measure ofinner retina and ganglion function. The MagD(μV)/Mag(μV) ratio thusprovides a measure of patient response normalized to that particulartest's electrical quality and thus minimizes inter-test variability. Inthe healthy eye, MagD(uv) should roughly equal Mag(uv). Thus, the closerMagD(μV)/Mag(μV) to unity, the more normal retinal function.

Omnifield resolution perimetry (ORP) (Sinclair Technologies, Inc, Media,Pa.) is a mesoptic threshold test of the central 20° diameter visualfield, measuring log MAR visual acuity by the correct identification ofLandolt “C” positioning at each intercept, rather than detection of alight source against a photopic background, as is accomplished withHumphrey field testing. The Omnifield is intended to mimic the mesopticenvironments of real-life vision tasks. At each presentation intercept,the Landolt C's are flashed on a monitor for 250 ms in one of 4positions. The patient signals theft recognition of the correct positionby deflecting a joystick on a response pad. An interactive algorithmadjusts the size of the Landolt Cs to determine a threshold of theletter size, below which the patient can no longer correctly respond.Testing k performed at fixation and at 17-24 intercepts out to 10°eccentricity. Outcomes from the visual field testing include the acuityat fixation, the best acuity at any intercept within 6° of fixation (theBA6°), the global macular acuity (GMA, the average acuity from allintercepts weighted inversely from fixation), and the visual area, (VA)the area under the curve plotting threshold acuity versus interceptarea, a measure of area of measureable visual acuity.

With reference to FIGS. 21 and 22, high contrast visual evoked potential(VEP) amplitudes of the tested 42 eyes range from 4.4-25.8 um (average10.9) before treatment, and 4.7-26.7 um (average 13.0) after treatment,for an average improvement of 2.1 uV, or 19%. Low contract amplitudesand latencies also improved, but were not visually significant in thissmall sample.

Table 1 below is a summary of the calculated differences (post-minuspre-treatment) of VEP measures.

TABLE 1 p- Variable Mean (SD) Median (IQR) value AMP, Low Contrast 0.290.45 (−2.10, 0.74 (N_(miss) = 1) (4.78) 2.90) AMP, High Contrast 2.220.85 (−1.10, 0.02 (N_(miss) = 1) (6.21) 3.00) LAT, Low Contrast −2.23−2.00 (−13.60, 0.47 (N_(miss) = 1) (19.82) 12.70) LAT, High Contrast−2.57 −2.45 (−6.80, 0.22 (N_(miss) = 1) (13.53) 4.00)

Table 1 shows the mean and median differences for the covariates ofinterest. Each row shows the difference (post-minus pre-treatment) AMP,or LAT, at the two contrast options. In order to test whether the meandifference is different from zero, linear mixed models predicting themeasure, using an indicator for time as a covariate, also adjusting forleft or right eye, and including a random patient intercept, were run.The p-values are those associated with the time (pre- versus post-)regression coefficient. A significant p-value indicates that the meandifference is significantly different from zero. Only AMP, HighContrast, is significantly different pre-treatment versuspost-treatment. This method accounts for inter-eye correlation.

Table 2, below, shows the linear regression analysis of the VEP results.

TABLE 2 Coefficient VEP measure (SD) p-value AMP, Low Contrast (N_(miss)= 1) −0.61 (0.14) 0.0004 AMP, High Contrast (N_(miss) = 1) −0.55 (0.21)0.02 LAT, Low Contrast (N_(miss) = 1) −0.69 (0.16) 0.0004 LAT, HighContrast (N_(miss) = 1) −0.56 (0.09) <0.0001

Table 2 shows the coefficients and p-values from six univariate linearmixed models, predicting the difference (post-minus pre-treatment) usingpre-treatment values as the covariate, with a random patient intercept.These models show the association between pre-treatment values and thedifference in the pre- and post-treatment values. A significantassociation exists in all models, and in the negative direction. Thisindicates that as the pre-treatment value increases, the differencedecreases, on average. N=number. SD=standard deviation. VEP=visuallyevoked potential.

With reference to FIGS. 23 and 24, PERG 24° Concentric Scan Mag(uv)amplitudes (42 eyes) ranged 0.51-1.64 uV (avg. 1.15) before treatmentand 0.7-1.93 uV (avg. 1.25) after treatment, for an average improvementof 0.10 uV (9%) (P=0.04). All other PERG measures were also improvedfollowing treatment, but not significantly in this small sample.

Table 3 below is a summary of the calculated difference (post-minuspre-treatment) Concentric ring PERG eyes.

TABLE 3 Variable Mean (SD) Median (IQR) p-value M(d)/M(uv) Ratio, 24Degree 0.00 (0.20) 0.00 (−0.12, 0.15) 0.93 M(d)/M(uv) Ratio, 16 Degree0.04 (0.20) 0.05 (−0.10, 0.17) 0.30 M(d) Measure, 24 Degree 0.05 (0.30)0.03 (−0.14, 0.27) 0.38 M(d) Measure, 16 Degree 0.04 (0.25) 0.05 (−0.11,0.20) 0.43 M(uv) Measure, 24 Degree 0.10 (0.33) 0.08 (−0.09, 0.33) 0.05M(uv) Measure, 16 Degree 0.03 (0.31) 0.05 (−0.13, 0.22) 0.45

Table 3 shows the mean and median differences (post-minus pre-treatment)for the covariates of interest. In order to test whether the meandifference is different from zero, linear mixed models predicting themeasure, using an indicator for time as a covariate, also adjusting forleft or right eye, and including a random patient intercept, wereperformed. The p-values are those associated with the time (pre- versuspost-) regression coefficient. A significant p-value indicates that themean difference is significantly different from zero. This methodaccounts for inter-eye correlation. Note that only the 24 degree M(uV)improved significantly following SDM NPT. M(d)=frequency response of thetime-domain averaged signal in microvolts (μV). M(uv)=reflects thesignal strength and electrode impedance of the individual test sessions.16 degree=16 degree retinal stimulus area. 24 degree=24 degree retinalstimulus area. IQR=interquartile range. SD=standard deviation.

Table 4 below is a summary of the calculated difference (post-minuspre-treatment (PERG) Concentric ring PERG testing.

TABLE 4 Coefficient Variable (SD) p-value M(d)/M(uv) Ratio, 24 Degree−0.42 (0.13) 0.005 M(d)/M(uv) Ratio, 16 Degree −0.65 (0.13) <0.0001 M(d)Measure, 24 Degree −0.39 (0.13) 0.006 M(d) Measure, 16 Degree −0.71(0.12) <0.0001 M(uv) Measure, 24 Degree −0.65 (0.13) 0.0001

Table 4 shows the coefficients and p-values from univariate linear mixedmodels, predicting the difference (post-minus pre-treatment) usingpre-treatment values as the covariate, with a random patient intercept.These models show the association between pre-treatment values and thedifference in the pre- and post-treatment values. Note that asignificant association exists, and in the negative direction. Thisindicates that as the pre-treatment value increases, the differencedecreases, on average. M(d)=frequency response of the time-domainaveraged signal in microvolts (μV). M(uv)=reflects the signal strengthand electrode impedance of the individual test sessions. 16=16 degreeretinal stimulus area. 24=24 degree retinal stimulus area. SD=standarddeviation.

With reference to FIGS. 25 and 26, ORP visual field testing wasperformed in 38/43 eyes before and after SDM treatment. In 6 of theseeyes (5 patients), the preoperative 20° diameter visual fields were fulland normal (400° recordable visual angle) before treatment. The visualarea by ORP at 99% mesoptic contrast ranged 51-400° (avg. 240°) beforetreatment, and 23-400° (avg. 280.7°) after treatment, for an averageimprovement of 40.7° (17%) (P=0.05). The BA6° and GMA were notsignificantly improved.

With reference to Table 5 below, results are shown of SDM NPT evaluatedby Omnifield resolution perimetry at 99% contrast.

TABLE 5 Variable Mean (SD) Median (IQR) p-v alue OMNI 99%, BA −0.08(0.32) −0.11 (−0.30, 0.16) 0.20 6 Degrees OMNI 99%, GMA −0.08 (0.32)−0.10 (−0.24, 0.02) 0.34 OMNI 99%,  48.08 (86.56)  32.00 (0.00, 104.00)0.04 Visual Area

Table 5 shows the mean and median differences (post-minus pre-treatment)for the covariates of interest. In order to test whether the meandifference is different from zero, linear mixed models predicting themeasure, using an indicator for time as a covariate, also adjusting forleft or right eye, and including a random patient intercept, wereperformed. The p-values are those associated with the time (pre- versuspost-) regression coefficient. A significant p-value indicates that themean difference is significantly different from zero. This methodaccounts for inter-eye correlation. Note that the visual area (VA) indegrees improves significantly following SDM NPT. OMNI=Omnifieldresolution perimetry. BA 6=best log MAR visual acuity within 6° offixation. GMA=global macular acuity. IQR=interquartile range.SD=standard deviation.

With reference to Table 6 below, a summary of the calculated differences(pre-minus post-) eyes evaluated by Omnifield resolution perimetry at99% contrast is shown.

TABLE 6 Variable Coefficient (SD) p-value OMNI 99%, BA 6 Degrees −0.59(0.14) 0.0006 OMNI 99%, GMA −0.30 (0.10) 0.01 OMNI 99%, Visual Area−0.24 (0.11) 0.03

Table 6 shows the coefficients and p-values from univariate linear mixedmodels, predicting the difference (post-minus pre-treatment) usingpre-treatment values as the covariate, with a random patient intercept.These models show the association between pre-treatment values and thedifference in the pre- and post-treatment values. Note that asignificant association exists in all models, and in the negativedirection. This indicates that as the pre-treatment value increases, thedifference decreases, on average.

As shown above, linear regression analysis demonstrated that the mostabnormal values prior to SDM NPT improved the most following treatmentfor nearly all measures, as shown in the Tables above. Panmacular SDMtreatment, in accordance with the present invention, in eyes withadvanced OAG improved key measures of optic nerve and ganglion cellfunction, indicating a significant neuroprotective effective treatment.The visual fields also improved, and there were no adverse treatmenteffects. Thus, generating a micropulsed laser light beam havingcharacteristics and parameters discussed above and applying the laserlight beam to the retinal and/or foveal tissue of an eye having glaucomaor a risk of glaucoma creates a therapeutic effect to the retinal and/orfoveal tissue exposed to the laser light beam without destroying orpermanently damaging the retinal and/or foveal tissue, and also improvesfunction or condition of an optic nerve and/or retinal ganglion cells ofthe eye.

As the collection of ganglion cell axons that constitute optic nerve liein the inner retina, with complex inputs other retinal elements andultimately from the photoreceptors of the outer retina, damage to, ordysfunction of, other retinal elements may thus lead to retrograde opticnerve dysfunction and atrophy. In accordance with this theory, providingtherapeutic treatment to the retina, in accordance with the presentinvention, may provide neuroprotective, or even therapeutic, benefits tothe optic nerve and ganglion cells.

Retinal ganglion cells and the optic nerve are subject to the health andfunction of the retinal pigment epithelium (RPE). Retinal homeostasis isprincipally maintained by the RPE via still the poorly understood butexquisitely complex interplay of small proteins excreted by the RPE intothe intercellular space called “cytokines”. Some RPE-derived cytokines,like pigment epithelial derived factor (PEDF) are neuroprotective.Retinal laser treatment may alter RPE cytokine expression, including,but not limited to, increasing expression of PEDF. Absent retinaldamage, the effect of SDM, in accordance with the present invention, is“homeotrophic”, moving retinal function toward normal. By normalizingRPE function, it follows that retinal autoregulation and cytokineexpression is also normalized. This suggests the normalization ofretinal cytokine expression may be the source of the neuroprotectiveeffects from SDM in OAG.

As the immediate effects of SDM in accordance with the present inventionon the retina are physiologic and cannot be assessed, in the short term,by anatomic imaging, measures of retinal and visual function independentof morphology are required, such as PERG. As the PERG improvements haveshown similarities to those previously reported in eyes with OAGresponding to IOP lowering, the similarity further suggests that SDM inaccordance with the present invention might be neuroprotective for OAG.

The VEP is generally considered the best measure of optic nervefunction, and improvement in optic nerve function by VEP followingtreatment would therefore be a strong indicator of a neuroprotectiveeffect. While PERG responses have been shown to improve following IOPlowering in OAG, VEP responses have not. It is notable, then, that VEPamplitudes improved, as indicated above, following treatment inaccordance with the present invention (SDM). Moreover, the recordablevisual area of the posterior 20° of the retina also significantlyimproved, and such ORP improvements may translate into improved everydayvisual function by treatment and therapy in accordance with the presentinvention.

Improvement in optic nerve function by selective sublethal lasertreatment of the RPE supports the idea that OAG may be, at least inpart, a primary retinopathy. Loss of REP-derived ganglion cellneurotrophism could account for the disconnect between IOP and OAGprogression. Laser-induced RPE HSP activation, by normalizing RPEfunction, in accordance with the present invention, might also normalizeRPE-derived neurotrophism and improve ganglion cell and optic nervefunction. A primary retinopathy may underlie some cases of OAG,accounting for disease progression despite normal or normalized IOP.Neuroprotective effects appear to be elicited by selective sublethal SDMtreatment of the RPE, in accordance with the present invention.

Although several embodiments have been described in detail for purposesof illustration, various modifications may be made without departingfrom the scope and spirit of the invention. Accordingly, the inventionis not to be limited, except as by the appended claims.

What is claimed is:
 1. A process for providing therapy for glaucoma,comprising the steps of: generating a plurality of spaced apart pulsedlaser light treatment beams each having power, wavelength, pulse length,and duty cycle parameters that provide therapeutic effect to retinaltissue without permanently damaging the retinal tissue; simultaneouslyapplying the plurality of laser light treatment beams to a firsttreatment area of the retinal tissue of an eye having glaucoma;simultaneously reapplying the plurality of laser light treatment beamsto the first treatment area after an interval of time of less than onesecond during a single treatment session; simultaneously applying theplurality of laser light treatment beams to a second treatment area ofthe retinal tissue which is spaced apart from the first treatment areaduring the interval of time; and repeatedly applying the plurality oflaser light treatment beams to the first and second treatment areasuntil a predetermined number of laser light beam applications to eachtreatment area has been achieved; wherein each of the laser lighttreatment beams has a wavelength greater than 532 nm, a duty cycle ofless than 10%, a pulse length of less than 500 milliseconds and a powerintensity of 100 watts to 590 watts per square centimeter.
 2. Theprocess of claim 1, wherein the second treatment area is spaced apartfrom the first treatment area to avoid thermal tissue damage.
 3. Theprocess of claim 1, including the step of applying the laser lighttreatment beams to treatment areas comprising retinal and/or fovealtissue of the eye.
 4. The process of claim 1, wherein the interval oftime is 1 to 3 milliseconds.
 5. The process of claim 1, wherein thefirst and second treatment areas each has 50 to 200 laser lightapplications applied thereto.
 6. The process of claim 1, wherein thelaser light treatment beams each have an intensity of 350 watts persquare centimeter.
 7. The process of claim 1, wherein the laser lighttreatment beams each have a duty cycle of 5% or less.
 8. The process ofclaim 1, wherein the laser light treatment beams each have a wavelengthbetween 532 nm and 1300 nm.
 9. The process of claim 1, wherein eachlaser light application comprises a single pulse of laser light of lessthan a millisecond in duration.
 10. The process of claim 1, wherein thegenerating step comprises the step of generating the plurality of laserlight treatment beams from a plurality of pulsed lasers having differentwavelengths.
 11. The process of claim 1, wherein the applying stepscomprise applying the laser light to the entire retina.
 12. The processof claim 1, wherein the laser light beams are applied to the retinaltissue without damaging the retinal tissue at the time of treatment. 13.The process of claim 12, wherein application of the laser light beams atthe time of treatment is not detectable visually or by FFA, FAF orSD-OCT at the time of treatment.